INTRODUCTION

 

Overview of VLC Training Program

 

Lung disease is a significant cause of mortality and morbidity in the United States (1).  While all other major causes of death are decreasing, age-adjusted mortality due to lung disease continues to rise. The prevalence of all forms of lung disease is also continuing to rise. For example, prevalence of wheezing and other asthma-like symptoms are currently reported to be as high as 20% in children.  Chronic obstructive pulmonary disease (COPD) is now the fourth most common cause of death, driven in part by the rapid rise of COPD deaths in women.  Northern New England, including Vermont, has a disproportionately high mortality and morbidity due to lung disease. For example, asthma is the leading cause of missed school days and work absenteeism in Vermont (2). Because of these facts, the establishment of lung disease research and training centers has become a strategic goal of the US Government, and in particular of the NHLBI, the State of Vermont (Healthy Vermonters 2010) and the University of Vermont (UVM).  Some of the strategic goals of NHLBI (3) are:

·        to develop improved methods of disease diagnosis that are minimally invasive

·        to develop new methods for detecting (example, biomarkers) inflammation associated with cardiovascular and lung disease

·        to develop and improve methods of treatment to reduce the disability and mortality burden accompanying cardiovascular and lung disease

·        to understand the genetic basis of individual responses to disease processes and therapy

·        to develop the scientific understanding necessary to be able to repair damaged tissue and organs

·        to develop innovative approaches to research and health care delivery using state-of-the-art scientific technology and communication/information tools

·        to generate mouse models appropriate for studying the development of cardiovascular and lung disease

·        to prepare clinical investigators (both MD and PhD) to perform research that translates basic ideas into human studies by providing training opportunities at entry and mid-career levels

·        to create a multidisciplinary research program to develop a systematic understanding of the complex interactions that underlie cell, tissue, and organ function and the alterations that produce lung disease

 

Historical perspectives Founded in 1791, the University of Vermont (UVM), located in Burlington, VT, is a state-supported institution offering a highly integrated academic environment for this training program.  The total undergraduate enrollment of UVM is about 8,000, and there are approximately 1,500 graduate and medical students.  The annual operating budget is $371 million with an endowment of $194 million and annual extramural grant support of $102 million, mostly from grants awarded to the faculty of the College of Medicine ($73 million).  This includes 4 Program Project Grants, 2 NCRR COBRE Grants (Center of Biomedical Research Excellence), NIH-supported Vermont Cancer Center and NIH supported General Clinical Research Center.  This places the UVM College of Medicine as 21st of 155 U.S. medical schools in grant dollars per faculty member.  Although UVM is a state institution, it receives less than 10% of its operating budget from the state, the lowest percentage of any state university.  It is, thus, extremely dependent upon extramural funding for the vitality of its research programs.

The Vermont Lung Center (VLC) was initiated at the College of Medicine, University of Vermont to create a multidisciplinary group of scientists undertaking collaborative research into the causes of and treatments for lung disease.  Scientific excellence is a centerpiece of the VLC.  However, scientific excellence can be achieved only by well-trained individuals working in an environment that is both stimulating and rigorous.

Mentoring is critical to achieving this goal. The senior faculty are skilled mentors who have collectively trained a large number of students, graduate students, postdoctoral fellows (both PhD and MD) and junior faculty.  In addition, the mentors will be advised and monitored by a Scientific Advisory Committee whose local members (Drs. Warshaw and LeWinter) are all prestigious investigators, scientific leaders and directors of training programs at UVM.  The Scientific Advisory Committee will also include two external advisors, both leading pulmonary scientists with international reputations. These external advisors are leaders of large research groups; and Jeff Fredberg who heads the Physiology Program at the Harvard School of Public Health and Galen Toews, Chief of Pulmonary and Critical Care Medicine, and director of a highly successful NHLBI T32 training grant at the University of Michigan.

The structure of our training program is formulated from our collective experience in teaching and mentoring. This structure emphasizes people, their training and their interactions, for in the end this is where the true value of any program lies.  We believe our plan has a high likelihood of success for achieving the one goal of the VLC program - to develop a critical mass of productive, funded and biomedical research scientists at UVM.

 

Central Themes of the Program

Vermont Lung Center

The Vermont Lung Center (VLC) is a multidisciplinary research entity with basic science laboratories on the main campus of UVM and a clinical trials unit at the Fanny Allen campus of FAHC. Its mission is to serve as a focal point for research and education in lung pathophysiology, as well as for new modalities for care of patients with lung diseases at both the UVM College of Medicine and the affiliated academic hospital, Fletcher Allen Health Care (FAHC). The VLC thus has a singular responsibility for leadership throughout a large geographic region, and has close ties to the 14 community hospitals that provide health care to patients with lung disease in a regional health care network established by FAHC. The unique nature of the rural and stable population of the region serves to create an ideal environment for the integration of basic, clinical and population–directed research related to diseases of the lung. The VLC will also take primary responsibility for outreach, public education and physician education related to diseases of the lung.

 

The original Vermont Lung Center existed at UVM for about twenty years, from 1972-1992. It started as a SCOR grant (HL-14212), but with time lost the necessary critical mass of investigators. Now UVM and FAHC are committed to its revival. To restart this program, Dr. Charles G. Irvin was recruited from the National Jewish Medical and Research Center and the University of Colorado Health Sciences Center in Denver, both highly regarded centers for asthma and lung disease research, to direct the VLC in 1998. The VLC was envisioned as a translational research group drawing scientists from both basic and clinical departments of UVM and FAHC with a focus on lung disease. The award in 1999 of the American Lung Association-Asthma Clinical Research Center (ALA-ACRC) (PI: Charles G. Irvin) to the VLC started the momentum. Even more momentum was added with the arrival in June 2000 of our new head of the Pulmonary Division, Dr. Polly Parsons from the University of Colorado School of Medicine. Dr. Parsons is a well-known expert in acute respiratory distress syndrome. Since 1998 we have added thirteen of the current proposed faculty made up of 8 physician Scientists and 5 Ph.D.’s (Figure 1). In 2000, Drs. Irvin and Bates were awarded a 5 year $6.7 million NCRR Center of Biomedical Research Excellence (COBRE) grant.  The purpose of this grant is to 1.) mentor and develop junior faculty and 2.) develop a multidisciplinary research center (see below for details).The VLC is still in the formative stages of development and has seen early success due to strong support from FAHC and UVM

Figure 1:  Growth (1998-2003) in VLC and UVM Pulmonary/Critical Care Division Personnel

 

Members of the VLC are drawn from several departments of the College of Medicine, including Medicine, Molecular Physiology and Biophysics, Pathology, and Immunobiology, and also other Departments and Colleges at UVM including; Agriculture and Life Sciences, Nursing, and Engineering and Mathematics. There are several standing meetings of the Vermont Lung Center faculty and Pulmonary Critical Care Medicine:  the research in progress research series, weekly clinical conferences and bimonthly faculty meetings.  There are currently 3 graduate students and 8 postdoctoral students as shown in Table 4.  They are mentored by several senior faculty.

 

Immunobiology Program

Joining this endeavor is the Immunobiology Program at UVM which is comprised of a core of 3 faculty in the Department of Medicine (Drs. Ralph Budd, Mercedes Rincon, and Cory Teuscher) and 1 faculty member from the Pathology Department (Dr. Sally Huber).  In addition there are additional immunologists that interact actively with this core, and include Dr. Laurie Whittaker in the Vermont Lung Center (VLC), Dr. Elizabeth Bonney in Ob-Gyn, and Drs. Jonathan Boyson and Abrar Khan in Surgery.  The Immunobiology Core faculty share a Program Project Grant AI45666 (Molecular Mechanisms of Th1/Th2 Development) which just received a score of 164 for its next five-year renewal application.  The projects involve studies of how NFAT, c-FLIP, Histamine Receptor-1 and gd T cells influence the cytokine environment.  Portions of this work involve studies of murine allergic airway disease and are being done in close collaboration with members (Drs. Irvin and Whittaker) of the Vermont Lung Center.  Some of this work is also done in collaboration with researchers at the nearby Trudeau Institute (Drs. Susan Swain, Markus Mohrs, and Laura Haynes) on the study of memory T cells and aging.  There is a weekly joint laboratory meeting of the Immunobiology faculty and members of the Immunobiology group frequently attend the weekly VLC research meeting.  There is also a weekly journal club and an Immunology Seminar Series.  There are currently 6 graduate students and 6 postdoctoral fellows in the laboratories of the core Immunobiology faculty.  As shown in Table 4 they are mentored by several senior faculty.

 

Organization Structure The director of the VLC, Dr. Charles G Irvin, reports directly to the Chairman of the Department of Medicine, Burton Sobel, MD. Dr. Irvin is also a member of the Division of Pulmonary Disease and Critical Care Medicine.  The director of the Immunobiology Group is Dr. Ralph Budd MD who ha a similar reporting structure.  The members of the Department of Pathology (Drs. Janseen-Heininger, Huber and van der Vliet) report to the Chairman of Pathology.

 

Translational Research and Scientific Discovery

 

The advances that have been realized in the molecular and genetic bases of medicine in the past two decades are nothing short of remarkable, yet the translation of these achievements into improved clinical care has been slow (4). Both investigators and policy makers have emphasized the urgent need to expand and support translational research. Typically physiologic in nature, translational research converts advances in molecular, cellular and genetic science into new methods of diagnosis or therapy (5).  One case in point was the realization that inflammatory cells release bronchoactive products into the extracellular space. This led to experiments in whole animals demonstrating the causal relationship between inflammation and airways hyperresponsiveness, the hallmark of asthma (6, 7). Current therapeutic approaches to asthma treatment are based on this proof-of-concept translation of cell biology to the bedside.

Translational research is thus the bridge between basic research and its practical application in creating new diagnostic procedures or drugs. Proposed projects start at the bench and will, at some point in time, end in the clinic. However, translational research is not just a one way street. Observations at the bedside have long driven investigators to delve into basic mechanisms of cellular physiology and genetics. Animal studies coupled with studies in cells and tissues will help validate and provide explanations for the clinical observations.  Further exploration of mechanisms and in particular the development of valid biomarkers will require relevant animal studies.  Clearly, without the successful translation of basic research findings to the bedside, the full value of the current revolution in fundamental biology will be lost. Equally important is the validation and provision of mechanistic explanations for clinical observations that will advance improvements in health care.

 

Research Environment

 

 “How do we train people to do translational research, and how do we carry out this research in the most effective manner?” Given the requirements of expertise in both basic and clinical research, together with modern pressures on health care providers, no one person can do it all. It requires a team approach where clinical and basic scientists work together, building on each others strengths and insights. There is also the need to instill in this new generation of biomedical scientists an appreciation for translational research through a team or collaborative approach.

We currently provide rich opportunities for young investigators to interact with collaborators as part of the next step in their career development.  However, each responsible investigator is expected, at the very least, to participate in a weekly laboratory meeting and the VLC Research-in-Progress meeting. This last meeting deserves some additional comment. The faculty of the VLC have experienced a myriad of meeting styles over the years, but most fail to provide an adequate forum for an investigator to present data, ideas or specific aims as they prepare a grant for submission. However, input from other scientists is most important at this stage. The VLC Research-in-Progress meeting, while less ad hoc than a lab meeting, is designed for presentation of new ideas without data, pilot data, half-finished projects, etc., with a strong emphasis on constructive discussion and critique from the audience.  On a given day the audience has MDs, PhDs and students in attendance.  Topics of both clinical and basic science relevance are presented. In addition, we recently conducted a full day retreat where the purpose was to further increase the interactions between clinical and basic scientists. This retreat was initiated and organized by the junior faculty.  A total of 9 proposals for clinical/translation projects were discussed and further developed We have developed “job descriptions” for both the mentors and trainees adapted from A Guide to Training and Mentoring in the Intramural Research Program at NIH (8).  As part of the COBRE program we also conduct a yearly retreat (Bolton Valley) organized similar to a symposium where young investigators (pre and postdoctoral trainees) present data in a formal format.

Statistical data demonstrate a significant influx of women into the sciences over the past decades (9).  In 1973, only 8.7% of doctoral candidates for scientific and engineering degrees were women; this number more than doubled to 21.6% in 1995. A recent report from the AAMC indicates that only 14% of tenured faculty and 12% of full professors in academic medicine are women (10).  The AAMC notes that “Only institutions able to recruit and retain women will be likely to maintain the best house staff and best faculty.” UVM is notable because of a strong history of promoting diversity and equality. 

Academic medicine, the cornerstone of the health care system, is threatened by the dramatic changes occurring in health care.  These changes jeopardize the whole future of talented investigators because extreme pressures are driving young physicians from a productive research career.  It is therefore incumbent on us to develop a special cadre of clinical investigators, both PhDs and MDs, who can directly translate the findings of basic research into improved patient care. It is precisely for this reason that the Department of Medicine of the College of Medicine at UVM has established the Faculty Scholar Training Program. This unique program provides qualified candidates (e.g. Dr. Scott Wagers) laboratory research and clinical subspecialty training sufficient to equip them for success as future faculty members and clinician scientists in academia. The point to be made here is that the faculty and upper level administration view research activities as a top priority and are prepared to be both creative and generous in achieving this goal.

 

 

Program Director

 

Dr. Charles Irvin, Ph.D. will serve as the director of this training program.  Organizationally, Dr. Irvin reports to the Dean of the College of Medicine and the Chairman of the Department of Medicine.  He will forward a report of these activities to the advisory committee (see below) where issues of progress, mentor selection and other issues will be decided.  Dr. Irvin received his Ph.D. from the University of Wisconsin, Madison in 1978 working under the direction of Dr. Jerome A Dempsey as an NIH pre doctoral student on an NIH training grant (HL07654).  From 1978-1980, Dr. Irvin was an NIH NSRA Postdoctoral  fellow with Dr. Peter T Macklem  M.D. at McGill University, Montreal, Quebec.  In 1980, Dr. Irvin was recruited by Dr. Reuben Cherniack M.D. to the Department of Medicine at the National Jewish Center and the University of Colorado Health Science Center in Denver, Colorado.  During his years in Colorado he was an active participant on the Colorado training grant (HL 07085) and was mentor for many of its trainees.  In 1998, he was recruited by Dr. Burton Sobel to head the Vermont Lung Center at the University of Vermont.  Dr. Irvin’s current research involves the pathogenesis and assessments of new treatments for asthma.  He has extensive experience in animal models of lung disease, lung mechanics, assessment of lung function and clinical research to include physiological investigation as well as multi-center trials.  Dr. Irvin has a long history (20 years) of training and mentoring physician scientists, both pediatric and adult.  All but one of his trainees are still in academics or contributing to scientific literature (see Table 4).  Of note, two current faculty and key personnel, Drs. Kaminsky and Wagers are both Dr. Irvin’s trainees.  Dr. Irvin’s tenure at three previous institutions of research, teaching, mentoring and administration have provided him extensive experience in leadership of a diverse, multidisciplinary group.  His success in rejuvenating the Vermont Lung Center (VLC) in the last five years is a prima facie example of his leadership skills.  The successful NCRR Center for Biomedical Research Excellence (COBRE) program is another tangible example of that leadership. Lastly as a Ph.D. significantly engaged in clinically oriented research, he provides an important role model for attracting Ph.D.’s into clinical research. 

                       

Senior Faculty:

Jason H.T. Bates, Ph.D., Research Professor of Medicine, 5% Effort

Research Interests:   Lung mechanics, asthma and lung injury, mathematical modeling in physiology

I have developed experimental techniques that allow us to precisely determine respiratory mechanical impedance in small animals. In association with Drs. Irvin and Wagers, I have been examining how the changes induced in the lung during acute allergic inflammation can lead to the observed hyperresponsiveness of mice to aerosolized challenge, thus making the link between structure and function in a way that allows us to explore some of the fundamental mechanisms that may underlie asthma. My laboratory has also been developing ways to extend our arsenal of investigative techniques in mice, including the measurement of lung volumes. Trainees involved in this project would learn a variety of experimental techniques in animal models of lung disease. I have also developed an active program in basic animal research into acute lung injury. Currently, I am exploring how lung injury induced in mice by various means (lavage, lipopolysaccharide instillation, hydrochloric acid instillation) can lead to an injury causing progressive gradual derecruitment of lung units during a period of mechanical ventilation. The experimental work has been undertaken in my laboratory by Dr. Allen, and I have developed a computer model capable of accounting for our results in collaboration with Dr. Irvin. An adjunct to this laboratory work is also being undertaken in critically ill patients, in association with Drs. Young and Parsons. I also supervise a PCCM fellow, Dr. Mohamed Turki, in the measurement of the airway pressures generated during manual ventilation of a mechanical lung analog. In collaboration with the New England Critical Care Organization investigators, I am measuring lung mechanics in mechanically ventilated patients, and intend to pursue this further in patients with lung injury. This again is an area well-suited to a research trainee.

 

 

 

Ralph Budd, Professor of Medicine; Director, Cell & Molecular Biology Program, 10% Effort

Research Interest:  Immunology and infectious/autoimmune diseases

The Fas-deficient lymphoproliferative (lpr) mouse develops an autoimmune disease resembling human lupus, as well as profound enlargement of lymph nodes.  We are studying the types of lymphocytes that accumulate in the absence of Fas-induced death.  In parallel studies, we are examining the alterations in Fas signaling caused by its natural inhibitor, c-FLIP.  We are examining this using overexpression of wild type and mutant forms of c-FLIP in cell lines and transgenic mice.  FLIP-transgenic mice manifest T cell hyperproliferation and a Th 2 cytokine bias.  In collaboarative studies with Dr. Irvin, FLIP-Tg mice manifest worse allergic airway disease. We are also investigating the function of γδ T cells in Lyme arthritis.  We have recently set up the murine model of Borreliosis and observe that adoptively transferred γδ T cells can promote a Th1 response in mice (BALB/c) that would otherwise mount a Th2 response.

 

Gerald S. Davis, M.D. Professor of Medicine, 5% Effort

Research Interests:  Pulmonary Fibrosis, Occupational Lung Disease, Asthma

This program studies the cell interactions and cytokine networks that regulate inflammatory cells and connective tissue matrix metabolism in the lung. Pulmonary fibrosis in mice caused by the inhalation of respirable crystalline silica particles serves as the test system for this research.  The current focus utilizes genetically modified mouse strains, monoclonal antibodies, and recombinant reagents to remove, augment, or replace specific cytokines. Working in collaboration with Drs. Rincon and Budd, a major thrust of the research is to understand how various lymphocyte phenotypes influence the pathogenesis of silicosis.  The role of trainees in this research will be to participate in ongoing studies and to develop independent but related projects.  Examples are the project related to “Mast Cells in Silicosis” recently completed by Daniel Paul, M.D. and the studies of “Forced Oscillation Lung Function Measurements in Silicosis in Mice” developed by Komgrit Chukiert, M.D. We are currently involved in three industry-supported treatment trials for patients with idiopathic pulmonary fibrosis or sarcidosis.  We are also involved in three investigator-initiated studies involving gene expression in pulmonary fibrosis, fourier analysis of lung sounds in interstitial disease, and the use exhaled breath condensate in scleroderma, sarcoidosis, and idiopathic pulmonary fibrosis.  Trainees participate in this research by developing projects of interest and following through the entire process of IRB application, subject recruitment, data collection, analysis and reporting.  Examples with current trainees include “Exhaled Breath Condensate Reflects Disease Activity in Idiopathic Pulmonary Fibrosis and Scleroderma” developed by Navdeep Singh, M.D., and the project “Exercise Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis” developed by Deepa Lala, M.D.

 

Sally Huber, Ph.D, Professor of Pathology, 5% Effort

Research Interest:   Immunology and infectious/autoimmune diseases

Coxsackievirus B3 is a picornavirus which most frequently causes cold-like symptoms, but can induce severe diseases including myocarditis, dilated cardiomyopathy, insulin dependent diabetes and hepatitis in some people. Pathogenic virus infections activate T cells expressing the Vg4 T cell receptor. Studies are continuing on the role of CD1 in initiating the innate immune response, why Vg4+ cells are needed for autoimmune CD8+ cell activation, and on the antigenic mimicry between the virus and heart antigens.  I am also interested in the role of CD4+ T cells in murine atherosclerosis. Evidence from both animal and clinical studies indicate that chronic inflammation is an important risk factor in atherosclerosis. C57Bl/6 mice, which inherently lack the major histocompatibility complex class II IE protein, develop strong IFNg responses, but transgenic C57Bl/6 mice in IE protein expression is restored are atherosclerosis-resistant.

 

Charles G. Irvin Ph.D, Professor of Medicine, Director Vermont Lung Center, 10% Effort

Research Interests/Projects:  Asthma, Lung mechanics and airway biology

 A long term interest of this laboratory is airway remodeling due to airway injury.  We have developed an animal (mouse) system of antigen induced alterations of airway structure and its link to function.   Currently we are examining the effects of fluticasone and salmeterol on these structured alterations and associated long-term increases in airways responsiveness.  In particular we are examining the role of lung volume and loss of parenchymal airway interdependence in collaboration with Jason Bates.  In collaboration with Yvonne Janssen-Heininger and Matthew Poynter, we are determining the ability of cationic proteins (e.g. eosinophilic MBP) to affect subepithelial fibrosis by JNK activation in the airway epithelium.  The role of the trainees in these projests will be to carry forward the projects and conduct the primary experiments.  As an example the MBP/JNK project is currently a Ph.D. candidate’s (Brian McElhinney) thesis project.  In collaboration with Drs. Kaminsky and Dixon I am involved in several clinical trials supported by the American Lung Association-Asthma Clinical Research Center Award and the NIH COBRE grant.  Projects slated to begin this year  are NIH funded, the first involves examination of the effects of placebo and education on asthma severity, the other investigates the treatment of gastroesophageal reflux. Another project is being developed to treat the upper airways of asthmatic patients with coexistent rhinosinusitis in collaboration with Shering Plough and will be the subject of a K23 award for Anne Dixon M.D.  Another grant for local funding of exhaled breath condensate has been submitted and Dr. Wagers, a trainee of Charles Irvin, wrote the grant. Trainees will participate in many ways and roles to include conduct of trials, submission and preparation of IRB forms, consents etc. and presentation of data.

 

Yvonne Janssen Heininger, Ph.D., Associate Professor, Environmental Pathology, 5% Effort

Research Interests:  Redox signaling and inflammatory lung disease

Altered redox signaling in airway epithelium is hypothesized to contribute to inflammatory signaling events. Numerous studies in asthmatics have demonstrated that the biochemistry of the gaseous signaling molecule, nitric oxide (NO) is altered. The bioavailability of functional NO appears to be decreased whereas the formation of toxic NO products such as peroxynitrite (ONOO-) and nitrogen dioxide (NO2) are enhanced. In three lines of investigation, we address the mechanisms by which the loss of NO constributes to the chronic activation of the transcription factor, nuclear factor kappa B (NF-kB). Via the contruction of a transgenic mouse, we have demonstrated that NF-kB activation in cells of the conducting airways is a major determinant for allergic airways inflammation. Thus altered redox signaling events in airways may be a contributing factor in promoting persistent NF-kB activation. We are assessing whether S-nitrosation in airways epithelium is compromised and will address whether augmenting S-nitrosation can attenuate allergic airways inflammation in the mouse. Since NO2 is formed in lungs from asthmatics and known to contribute to inflammation and airway injury, we are studying the mechanisms by which NO2 interacts with target cells. Specifically we are investigating the role of death receptors, and the c-Jun-N-terminal kinase pathway in NO2 induced cell death. Through the use of transgenic and knock-out mice, and the use of specimens from patients with asthma we are gaining important insights about the role and the relationship of altered redox signaling in the airway epithelium and aggravation of inflammation that occurs in asthmatics.

 

David A. Kaminsky, M.D., Associate Professor of Medicine, 10% Effort

Research Interests:  Pulmonary function testing, lung mechanics, asthma

The main focus of my research program is investigating the alterations in airway and parenchymal lung mechanics in subjects with asthma.  In collaboration with Drs. Irvin and Bates, this research involves the forced oscillation technique in conjunction with computed tomography imaging of the lung.  In addition, associated changes in airway cellular and molecular constituents are measured by use of induced sputum and exhaled condensate analysis. Dr. Turki, a fellow in PCCM, is measuring pressure-volume characteristics in these subjects, and Dr. Wagers, also a fellow in PCCM is involved in the collection and analysis of induced sputum and exhaled breath condensate samples. I also collaborate with Drs. Rincon and Wagers in investigations into the role of human epithelial cell IL-6 in directing TH2 differentiation in asthmatic subjects.   In another trial the expression of various NF-kB regulated epithelial genes is being investigated in patients with COPD.  Epithelial cells are collected by bronchoscopy, and Dr. Singh is directly involved in this aspect.  The cellular analysis is being conducted by Drs. Poynter and Jansenn-Heininger.   I am directly involved in the ongoing trials of the Asthma Clinical Research Network, in conjunction with Drs. Irvin and Dixon and I am the local PI of a Phase II trial of a retinoic acid derivative in patients with COPD, a study that involves bronchoscopy and fellows Drs. Leavey, Turki, Lala and Ganatra.  I am currently working with Dr. Leavey on a study of the diagnostic utility of DLCO/VA and mentoring a resident, Dr. Fought, on the effects of high altitude on spirometry.  Finally, I am working on a research educational program involving office spirometry in the community in which fellows may participate.

 

Polly E Parsons MD, Professor of Medicine, Chief of Pulmonary and Critical Care Medicine, 10% Effort

Research Interests:  Pathogenesis of acute lung injury

In conjunction with the NIH:NHLBI ARDSnetwork for clinical trials, I am currently measuring several biomarkers to measure the impact of low tidal volume ventilation on the plasma levels of inflammatory cytokines and biological markers of endothelial and epithelial injury and  to determine if baseline measurements of these biomarkers predict morbidity and mortality and correlate with physiologic indices of lung function and severity of nonpulmonary organ dysfunction.  In conjunction with Drs. Bates, Wagers and Allen, studies to evaluate the significance of D-dimer in exhaled breath condensate in patients with ALI are also in progress. Currently Drs. Wagers and Singh, both fellows in PCCM, are working with Drs. Davis and Irvin to validate the collection methods and biomarker measurements in exhaled breath condensate.  Using their techniques, D-dimer levels in breath condensate from patients with ALI/ARDS will be correlated with biomarkers including plasma vWf and with physiologic indices of lung injury including dead space ventilation in patients with ALI/ARDS. I also serve as a primary investigator in the critical care trials performed by the Northern New England Critical Care Organization.

 

Mercedes Rincón, Ph.D, Associate Professor of Medicine, 10% Effort

Research Interest:  Immunology and infectious disease

One of the main areas of research of our group is to determine the regulation and role of the JNK and p38 MAP kinase signaling pathways in the development, activation, differentiation and death of CD4+ and CD8+ T cells. We have generated several genetically manipulated mice to inhibit or activate these signaling pathways in T cells. These mouse models not only have been used to determine the role of JNK and p38 MAP kinase in T cells in vitro, but also to examine their role in in vivo immune responses such as that against flu virus or Borrelia burgdorferi infection. We are also studying the role of IL-6 in the differentiation of Th1 and Th2 effector cells and its molecular mechanisms. We have shown that IL-6 inhibits Th1 differentiation by inducing SOCS1 gene expression to block IFNδ signaling. IL-6 also promotes Th2 differentiation by activating NFAT and inducing early gene expression. We have also examined the role of IL-6 in the development of Th1 immune responses against B. burfdorferi infection.  A third area of research is the regulation and role of NFAT transcription factors during fetal thymocyte development and differentiation of CD4+ T cells in the peripheral immune system. We have generated transgenic mouse models to examine in vitro and in vivo NFAT transcriptional activity, and the effect of inhibition of NFAT in T cells in vitro and in vivo in response to Nippostrongylus brasiliensisas well as in an asthma model with Dr. Irvin.

 

Burton Sobel, M.D., Professor of Medicine, Chairman of the Dept. of Medicine, 5% Effort

Research Interest:  Effects of diabetes on the cardiovascular system

Research trainees in our laboratory are participating in studies designed to elucidate pathogenetic mechanisms underlying diabetic vascular disease and airway inflammation particularly with respect to the influence of insulin, cytokines, and other mediators influencing signal transduction on the expression of fibrinolytic system proteins and their role in pathogenesis.  They gain experience in biochemical, cellular biological, and molecular biological methods used to define regulation of gene expression of the proteins participating in the system and modulation of gene expression with small molecules, transfection, and the use of transgenic mice.  The experience gained should be relevant to a career in vascular biology, pulmonary biology, and myocardial biology for individuals who aspire to academic, investigative, scholarly, and clinical excellence.  The overall objective of our ongoing work is to identify the impact of several specific factors on cellularity and hence vulnerability to rupture of evolving atherosclerotic plaques and on pulmonary fibrosis.  Plaque vulnerability is associated with several conditions in which plasminogen activator inhibitor type-1 (PAI-1) is overexpressed as well.  Accordingly, our work is designed to:  1) delineate the impact of increased expression of plasminogen activator inhibitor type-1 (PAI-1) by vascular smooth muscle cells (VSMC) on celluarity of neointima in mice deficient in apolipoprotein E (ApoE); 2) characterize the influence of gender on the composition of developing atheroma in ApoE knockout, VSMC PAI-1 overexpressing mice fed a high fat diet as a function of time; 3) elucidate the impact of the magnitude of hyperlipidemia on neointimal VSMC cellularity in the same strains of transgenic mice; and 4) delineate the extent to which VSMC expression of an enzymatically inactive mutant of human tissue-type plasminogen activator capable of inducing a dominant negative state with respect to PAI-1 in VSMC. We are (in collaboration with Drs. Irvin and Wagers) actively engaged in research aimed at defining the role of PAI-1 in the development of airway subepithelial fibrosis.

 

Douglas Taatjes, Ph.D, Professor Department of Pathology, 5% Effort

Research Interest:  Microscopy-based study of cardiovascular disease and lung pathology

Together with Drs. Burton Sobel and David Schneider, Department of Medicine, we are investigating the role which PAI-1 may play in atherosclerotic lesion formation. Lesion formation is assessed by multicolor confocal scanning laser microscopy following incubation of sections with markers for lipid, collagen, smooth muscle cells, macrophages, and total cellularity. Together with Dr. Ted Bovill, Department of Pathology, we are using atomic force microscopy to study events in blood clot formation. Atomic force microscopy allows us to image these events in a hydrated state, with resolution approaching that of electron microscopy. We have imaged human fibrinogen in fluid, and compared its' size and shape to that previously determined by electron microscopy. All of these studies share the common goal of gaining insight into the mechanisms underlying the formation of cardiovascular diseases, with the ultimate goal of recognizing areas for pharmaceutical intervention. We are also working together with Drs. Yvonne Janssen-Heininger Daniel Weiss to use imaging techniques to investigate subcellular effects of environmental agents on lung cells. Both cultured lung cells and in vivo models are used to assess the effects of eosinophil EPO on cell signaling pathways, cell proliferation, and apoptosis. These studies predominantly involve fluorescent probes applied to cells, which are then visualized by confocal scanning laser microscopy, digital wide-field fluorescence microscopy, or laser scanning cytometry. The role of the trainees in both these studies is to conduct research related to defined projects, and to write-up and present their work at scientific meetings.

 

Cory Teuscher, Ph.D Professor of Medicine, 5% Effort

Research Interest:  Immunogenetics and infectious/autoimmune diseases

The major focus of the research effort in my laboratory is the identification and characterization of non-classical immune response genes controlling susceptibility and resistance to immunopathologically mediated diseases.  These include murine models of both infectious and autoimmune disease.  The overall strategy is to use reverse genetics to first genetically map the loci of interest within the mouse genome followed by a traditional positional candidate gene cloning approach.  With respect to infectious diseases, we have mapped a number of loci that control the quantitative variation in a number of the component phenotypes seen in murine Lyme disease.  Similarly, we have identified quantotatve trait loci (QTL) which govern quantitative phenotypic variation in a number of traits associated with Theiler’s murine encephalomyelitis induced demyelination, an infectious disease model for multiple sclerosis (MS). The autoimmune disease models that we study are experimental allergic encephalomyelitis (EAE), experimental allergic orchitis (EAO), and day three thymectomy induced autoimmune ovarian dysgenesis (AOD).  For each of these models we have identified a large number of QTL many of which co-localize with genetic regions implicated in other autoimmune disease models.  This lead us to hypothesize that there may be both common and disease-specific loci that regulate susceptibility to immunopathologically mediated phenotypes.  This was proven true for Bphs, an autoimmune disease susceptibility gene implicated in both EAE and EAO when it was identified as histamine H1 receptor.  Bphs/Hrh1 controls both the induction phase of the immune response as well as the effector phase in that it governs susceptibility to Bordetlla pertussis toxin induced hypersensitivity to histamine, an intermediate phenotype underlying both diseases.  Similar studies are underway for the major QTL that we have mapped to date for both the infectious and autoimmune disease models under investigation.

 

 

 

Albert van der Vliet Ph.D, Associate Professor Department of Pathology, 5% Effort

Research Interests:  Nitric oxide and oxidants in airway inflammation

Many of the cellular effects of cigarette smoke can be attributed to unsaturated aldehydes, prominent components of indoor and outdoor pollution (e.g. tobacco smoke) which are also formed endogenously by lipid oxidation during inflammatory events in the lung. Because cigarette smoking (or exposure to secondhand smoke) is believed contribute to chronic inflammation such as in asthma or emphysema, and thus worsen lung function, we are investigating the potential effects of these aldehydes on processes that regulate inflammation. Exposure of isolated neutrophils to such aldehydes affects several neutrophil properties, including the execution of the constitutive apoptosis pathway, which is critical in the resolution of inflammation.  We are studying the cellular mechanisms by which aldehydes may cause such effects, by identifying specific cellular targets for these aldehydes, using proteomics approaches. In collaboration with Drs. Janssen-Heininger and Irvin, we are investigating the regulatory effects of nitric oxide (NO) on airway inflammation, with special emphasis on NF-κB signaling. NO is known to regulate inflammation by several mechanisms, and such regulatory properties may be affected by its oxidative metabolism during inflammation. Many of the biological effects of NO are mediated by S-nitrosation of specific target proteins, and we have evidence that NO can regulate inflammation by direct nitrosation of critical components of the NF-κB pathway.  We are developing tools and procedures to more accurately assess protein S-nitrosation in in vivo, and to identify specific target proteins, using proteomics techniques (2-D electrophoresis, mass spectrometry, etc.). We are exploring the biological significance of such an oxidant activation mechanism in relation to airway inflammation and remodeling, using analytical approaches to characterize and identify oxidative modifications in these enzymes in relation to their activation.   Trainees in my lab typically are currently developing derivatization and detection strategies for nitrosated or aldehyde-modified proteins and they are investigating the role of NOS2 on various cell signaling pathways. They present their work at scientific meetings and are involved in manuscript and grant writing.

 

Junior Faculty:

Gilman Allen, MD, Assistant Professor of Medicine, 5% Effort

Research Interests:  Pathogenesis and mechanical manifestations of ALI and Ventilator-Induced Lung Injury

One primary interest in our laboratory is the pathogenesis of acute lung injury (ALI) and how specific milestones in its development translate into derangement in lung function.  We have developed two separate models of ALI in mice, one in which injury consists of neutrophil infiltration with minimal alveolar edema or hemorrhage, and another model which is characterized by more severe alveolar edema and hemorrhage, with hyaline membrane and fibrin accumulation.  The ultimate goal is to investigate the mechanisms that link different pathologic components of ALI to typical lung mechanical manifestations, such as decreased compliance and disrupted gas exchange.  We have also begun to utilize our newly developed models of ALI in mice to investigate the potential injurious effects of different recruitment strategies during prolonged mechanical ventilation. In collaboration with Drs Irvin and Wagers, Dr. Bates and I have been investigating the role of fibrin in the pathogenesis of our mouse models of ALI. We have demonstrated a direct correlation between levels of the fibrin degradation product, D-dimer, within bronchoalveolar lavage fluid (BALF) and the degree of lung function derangement.  This suggests that alveolar fibrin accumulation is a critical determinant of lung mechanical function in ALI.  We currently plan to further investigate this hypothesis through translational studies in patients with cardiogenic and non-cardiogenic edema.

 

Anne E. Dixon, M.D., Assistant Professor of Medicine, 5% Effort

Research Interests:  Asthma, Interaction between upper airway disease and asthma

A long-term interest is the effect of active upper airway disease (rhinitis and sinusitis) on the control of asthma.  We are working with the American lung Association- Asthma Clinical Research Centers and collaborating with Schering-Plough to study the effects of treating upper airway disease on the course of asthma.  We are also developing techniques to study epithelial activation in the upper and lower airway.  The ultimate goal is to investigate the mechanisms that link upper airway disease with lower airway hyperreactivity. Trainees will participate in submission and preparation of regulatory paperwork (Institutional Review Board and consent forms), conduct of trial visits and collection of data, and data analysis and presentation.  I am currently participating in several clinical trials supported by the American Lung Association-Asthma Clinical Research Center Award. Trainees will participate in these trials (patient recruitment, conduct of trial visits, collection of data and generation of case report forms) to gain experience in the conduct of large multi-center trials.

Theodore W. Marcy, MD MPH, Associate Professor of Medicine, 10% Effort

Research Interests:  Tobacco control, health services research in preventive services

 I am conducting studies that will provide the foundation for a proposal for a randomized controlled trial of computer mediated clinical decision support systems (CDSSs) to improve implementation of evidence-based guidelines for tobacco use and dependence treatment.  CDSSs can be designed to indicate a patient’s smoking status, to provide detailed guideline recommendations, to link a patient with community resources, and to produce patient-specific handouts.  Despite their potential, CDSSs are not widely used by physicians or by the majority of health care organizations. This project uses surveys to define the needs of physicians, their familiarity with information technology, and their health care environment.  CDSSs for smoking cessation will be designed using this information and then adapted with further feedback from physicians and clinic administrators through focus groups and a pilot test of the adapted CDSS.  I am currently mentoring two PCCM fellows on a quality improvement project that will retrospectively investigate physician patterns of use of CT angiograms for evaluating for pulmonary emboli.  This study will provide information for a plan of education of physicians on algorithms for screening for pulmonary emboli.

 

Matthew E. Poynter, Ph.D, Assistant Professor of Medicine, 5% Effort

Research Interests:  Airway epithelial cell signaling in allergic and infectious lung disease

The research program of my laboratory is focused on elucidating the important roles of intracellular signaling cascades activated by the airway epithelium to mediate the integration of innate and adaptive immune signaling in lung health and disease.  To this end, murine models of allergic airway inflammation and hyperresponsiveness (asthma-like), Cystic Fibrosis, infection, using bacterial products in lieu of live organisms, and inhalation of the oxidant gas, nitrogen dioxide (·NO2) are employed.  Similarly, in vitro airway epithelial cell culture techniques are employed to further study cell signaling in the context of a single cell type.  We have focused on signaling through the NF-kappaB (NF-κB) pathway, leading to transcriptional upregulation of inflammatory cytokines and enzymes, pro- and anti-apoptotic genes, and augmented expression of numerous other immunomodulatory proteins.  The airway epithelium also contributes in a very important manner to adaptive (antigen-specific) immunity.  The barrier formed by bronchiolar epithelial cells is bathed in mucosal secretions containing immunoglobulin, which participate in the clearance of microbes from the airway.  Only IgA and IgM are present in the mucosal secretions because the polymeric immunoglobulin receptor (pIgR), expressed by bronchiolar epithelium, actively transports these classes of immunoglobulin from the basal surface of the epithelium to the airway.  Importantly, pIgR expression is augmented through activation of NF-κB, which may be taken advantage of to elicit immunoprotection against inhaled microorganisms and toxins.  These studies will involve evaluation of novel prophylatic inhaled immunization strategies, using CpG DNA as a mucosal adjuvant.  It is anticipated that this strategy will afford both systemic and secretory immunoglobulin-mediated protection against a broad range of agents and may be employed for delivery of tumor vaccines.    The role of the trainees involved in these projects will be to conduct the primary experiments, thereby taking the projects forward.

 

Benjamin T. Suratt, MD Assistant Professor of Medicine, 5% Effort

Research Interests:  Neutrophil biology, acute lung injury, inflammatory complications of hematopoietic stem cell transplantation, stem cell biology

A long term interest of this laboratory is neutrophil behavior in the development of acute lung injury.  We have developed several animal (mouse) models of neutrophil circulatory kinetics.  The ultimate goal is to investigate the mechanisms of neutrophil handling in the marrow as they apply to already circulating neutrophils, and how circulating neutrophil heterogeneity is maintained in health, or deranged in processes culminating in lung injury.  Currently we are examining the role of the CXCR4/SDF-1 chemokine axis in regulating circulating neutrophil kinetics and, in particular, marrow retention for re-release or clearance.  We have recently begun collaborative projects with Drs. Bates and Allen, investigating the influence of mechanical ventilation on circulating neutrophil behavior and heterogeneity, particularly during the development of ventilator induced lung injury.  A further line of investigation we are pursuing is the effect of marrow ablation and reconstitution on the subsequent regulation of circulating neutrophil homeostasis.  The role of the trainees in these projects will be to carry forward the projects and conduct the primary experiments.  In collaboration with Drs. Weiss, Poynter, and Whittaker, our lab is examining the incorporation of marrow-derived stem cells in the epithelium and endothelium of the adult lung (chimerism).  Our efforts are directed at understanding the mechanisms leading to pulmonary chimerism, and its potential therapeutic role in diseases such as cystic fibrosis.  The role of the trainees in these projects will be to carry forward the projects and conduct the primary experiments.

Scott Wagers, MD Assistant Professor of Medicine, 5% Effort

Research Interests:  Asthma, Lung mechanics and airway biology

We have an interest in the fibrinolytic system in airway inflammation both in terms of its effects on airway remodeling and physiology.  Working with a mouse model of airway inflammation as a tool for investigating both biochemical and physiologic changes, we apply state of the art techniques, forced oscillations, to determine lung mechanics in mice. We have also developed a transgenic mouse and utilize techniques of quantitative histology, immunohistochemitry and protein biochemistry. The findings from these studies will serve as the basis for studies in patients with asthma and ALI.  Trainees will have opportunities to participate in both basic science as well as the clinical aspects of this project.  We are currently embarking on a project to evaluate exhaled breath condensate, a technique that holds promise as a noninvasive technique for sampling the lung but the reliability, optimization and reproducibility of this technique remains to be determined. Trainees will have the opportunity to participate in the development of this technique as well as the ability to use this technique to test hypotheses they themselves generate.  

 

Daniel J. Weiss M.D., Ph.D, Assistant Professor of Medicine, 5% Effort

Research Interests:  Gene and stem cell therapies for lung diseases

A long term interest of this laboratory is developing more effective techniques of gene transfer to lung airway epithelium for purposes of therapeutic correction of defective lung epithelium.  We have developed a novel means of enhancing gene delivery using perfluorochemical liquids.  More recently we have expanded this to use of nebulized perfluorochemicals, a more feasible potential clinical approach.  We are also examining transfer of DNA encoding for relevant therapeutic substances including CFTR and IL-10 in cell culture as well as in small animal (mouse) and pre-clinical (non-human primate) models.  More recently, we have developed cutting edge investigations into whether cells from adult bone marrow can localize to and transform into mature functional airway and alveolar epithelial cells.  The goal is repair and repopulation of defective lung epithelium with normal epithelial cells derived from the bone marrow cells.  Target diseases for both gene and bone marrow cell therapies include cystic fibrosis, asthma, and acute lung injury. These are multi-faceted studies using state of the art cell and molecular biologic techniques and include work done in present and planned collaborations with Drs. Allen, Bates, Goncz, Irvin, Janssen-Heininger, Poynter, Rincon, Suratt, Taatjes, Whittaker.  Current trainees include Roberto Loi (post-doctoral, start 7/03) Robert Prenovitz (pre-doctoral, start 9-03), and Melissa Catenacci (pre-doctoral, start 9-03).  Trainees participate in independent benchtop research including study design, institution, analyses, interpretation, and presentation of research questions and results.

 

Laurie A. Whittaker, MD, Assistant Professor of Medicine, 5% Effort

Research Interests:   Airway inflammation in asthma and Cystic Fibrosis

Persistent inflammation is a prominent feature of CF airways disease.  The role of lymphocytes in this process is not well understood.  The cystic fibrobsis transmembrane regulator (CFTR) is present on lymphocytes, implicating them as contributors to lung disease pathogenesis.  Little is know about lymphocyte function in CF.  We are interested in examining the effects of different antigen/adjuvant response in a murine model of CF (ΔF508 mouse) as it pertains to CD4 Th1 and Th2 lymphocyte development.  We are also interested in the in vivo response of the CF airway to inflammation mediated by these cell types.  In collaboration with Drs. Budd and Rincon and mentored by Dr. Irvin, we plan to study the effects of lymphocyte mediation on lung function in these animals.  The role of trainees in this project will be to carry forward the efforts and conduct the primary experiments.  In conjunction with Dr. Dan Weiss, we are performing a study in patients with CF to determine if adequate insulin absorption occurs after a single administered dose of inhaled insulin.  If appropriate we hope to expand to a full scale clinical trial.  The role of trainees in such a trial would include submission of IRB forms, consents etc. and collection, analysis and presentation of data.   

Michael Young, MD, Assistant Professor of Medicine, 5% Effort

Research Interests:  Acute lung injury, Impact of organization on medical outcomes in the ICU

To promote clinical research in the ICU setting we formed a clinical consortium of intensive care units in northern New England that include Dartmouth Hitchcock Medical Center and Maine Medical Center. Our first project as a consortium examined the variability of tidal volumes used to mechanically ventilate patients with ALI/ARDS. Despite the findings that small tidal volumes reduce mortality we observed that clinicians continue to use very large tidal volumes to ventilate the great majority of patients with ALI/ARDS. Our findings have contributed in a constructive way to the ongoing controversy surrounding the ARDS network. Two of our PCCM fellows, Drs Leavey and Wagers assisted with patient screening, data collection and analysis. The second clinical issue under exploration by our clinical consortium of northern New England ICUs is measuring the variability and reliability of the rapid shallow breathing index (RSBI), a widely used predictor of weaning success or failure. Dr. Ganatra a fellow in PCCM and Dr. Arentz, medical resident at UVM are involved in project conception, obtaining informed consent, execution of the protocols and data analysis.

 

Training

 

Introduction The following are presented as examples of a training curriculum for first predoctoral and then postdoctoral training.  Predoctoral training is less flexible and, of course, dictated by the requirements for the degree.  Predoctoral students, for the most part, will be attracted through the Cell and Molecular Biology (CMB) Graduate Program but a more inclusive generic (umbrella) graduate program for UVM will be in place by 2004 and all graduate students at the College of Medicine will then come through this program.  Postdoctoral training will be more custom-built depending on the needs of a given trainee.  These exact needs will be determined by the trainee and mentor(s) and monitored/evaluated by the executive committee(see below).

 

Predoctoral training (CMB training)

Courses Students of CMB devote a substantial proportion of their time to formal course work during the first year.  Salary support and health care benefits during the first year are provided by, respectively, the Graduate College and College of Medicine.  All recipients are required to be a teaching assistant (TA) for one course (6 hours weekly for one semester).  Additional time is devoted to four-month rotations through three laboratories of prospective thesis advisors.  Students generally enter a specific laboratory after their first year and funding is provided through their laboratory advisor, from the grant.  Candidates will be considered for admission to the Training Grant Program after completion of their first year. Trainee support from the Program will not exceed five years.  The graduate student course load is generally 10 credits per semester during the first two years.  Course requirements for admission to the Training Program and a sample curriculum for the first two years are listed below. 

 

Undergraduate Course Pre-requisites. The following courses are required before entering the Training Grant: Calculus, Inorganic and Organic Chemistry, General Biology and Physics.  The following courses are recommended before entering the Training Grant program: Microbiology, Immunology, Genetics, Statistics and Physical Chemistry.

 

Sample Curriculum of Year 1 and 2 in CMB:

 

 

Semester 1

Semester 2

Credits

Course

Credits

Course

1

CMB Seminar

1

CMB Seminar

3

Biochemistry- 301

3

Biochemistry- 302

3

Cell Biology- 301

3

Cell Biology- 302

1

Pathology 275 (Ethics in Scientific Research)

2

Doctoral Research

2

Doctoral Research

 

 

YEAR 02

Semester 1

Semester 2

Credits

Course

Credits

Course

3

Introductory Immunology 223

 

 

1

CMB Seminar

1

CMB Seminar

3

Intro to Lung Biology

3

Advanced Lung Biology

3

Doctoral Research

2

Doctoral Research

 

 

 

 

In years 3, 4 and 5, students will, to a large extent, emphasize doctoral thesis research while taking the required advanced seminars.  Others have elected to register for credit or audit additional courses.  Basic required didactic lecture course work is typically completed by May of the first year. 

Note: Course in bold are required for the CMB Program.

 

Electives (Pre and Postdoctoral)

Introduction to Lung Biology (Drs. Irvin, Parsons, Bates and VLC) We are planning to develop a 3-credit survey course covering various topics of lung biology.  This course will be offered every other year.

Advanced Topics in Lung Biology (VLC faculty) we are planning to develop a course in advances topics of lung biology coupled with our visiting scientist series.  This course will be offered on alternating years with the Introduction to Lung Biology and be most attractive to postdoctoral fellows.

Introductory Immunology 223 (offered every other year, 3 credits, Drs. Gerald Silverstein, Ralph Budd, and Mercedes Rincon) A survey of the main themes of immunology, including lymphocyte development, antigen receptor gene rearrangement, adaptive versus innate immunity, MHC restriction, naïve versus memory lymphocytes, cytokine production, and applications to allergy, transplantation, autoimmunity, and infectious diseases.  If students have had an equivalent undergraduate course, they may place out of this course.

 Advanced Immunology 330 (offered every other year, 3 credits, Drs. Budd, Rincon, Teuscher, and Huber at UVM) A literature-based course of an in-depth analysis of signal pathways and gene regulation involved with lymphocyte selection, cell migration, cytokine gene regulation, generation of immune memory, and apoptosis.      

Transcriptional gene regulation (Dr. Mercedes Rincon):  An in-depth literature-based analysis of transcription factors, method of function, chromatin structure, and methods used to study these processes.  There is also a grant writing element to this course.

Programmed Cell Death (Dr. Ralph Budd):  A detailed didactic and literature-based study of death receptors, caspase-signaling, mitochondria function, in normal development, immune regulation, cancer, and infections.

Immunogenetics (Dr. Cory Teuscher):  A state-of-the-art study of the theory and actual methodology used for mapping disease susceptibility loci for infectious and autoimmune diseases.

Immunopathology (Dr. Sally Huber):  This uses current literature to evaluate the pathogenic mechanisms of tissue injury and immune response in diseases such as asthma, lupus, rheumatoid arthritis, type I diabetes and atherosclerosis. Emphasis is placed on how environmental factors such as infections or chemical exposure can initiate immune diseases, or, as in the case of asthma, may be protective.

Genetic Manipulation of Mice (Dr. Mercedes Rincon):  A week long intensive course with external guest lecturers.  This course is next planned for the 2004-2005 academic year.

Lung Mechanics Workshop (Drs. Bates and Irvin):  For the last three years Drs. Irvin and Bates have conducted a two day workshop on the principles of lung mechanics complete with hands on sessions.

Mathematics for Biologists (Dr. Jason Bates):  A survey of mathematical techniques for biology and medicine, including calculus, differential equations and statistics.

Workshop in grant writing (Dr. Charles Irvin):  This is a survey of grantsmanship.  Part of this will include participation in actual presentations and critique sessions by program investigators to assist trainees in writing their own grants (summer, 2003).  This course is given on alternate years.

Mentoring  Workshop (Dr. Charles Irvin)  A half-day workshop on mentoring issues and approaches will be held every other year. This is a required course for all trainees and mentors. 

Presentation Skills Workshop (Dr. Charles Irvin) Conducted as a two half-day workshop.  This course is given every other year (fall 2003).

Ethics in Scientific Research Course This is required for all graduate programs in the biological sciences at UVM and is coordinately taught by all training grant directors at UVM. This is required of all trainees.

Seminar Series (Predoctoral and Postdoctoral)

There are weekly seminar series at UVM in related fields that are available to all students.  These include: Biochemistry, Physiology and Biophysics, Pharmacology, Neurosciences, Environmental Pathology (emphasis on cellular signaling) and Vermont Lung Center (emphasis on lung research both clinical and basic). Other important interest groups that meet regularly include:          

Cell Signaling/Environmental Pathology:  Mechanisms of receptor-based signal transduction are of interest to many of our training faculty including Drs. Irvin, Bates, Poynter, Janssen-Heininger, Rincon, Budd, and Teuscher, who are also members of a cluster of "Receptors and Biotechnology EPSCoR Group” (Experimental Program to Stimulate Competitive Research) provides funds to individual junior faculty's research, to support seminars and infrastructure development.

Molecular Biology Journal Club and E-mail Discussion Group:  This discussion group was started by Dr. Jan Nicklas (Vermont Cancer Center) a few years ago, and has incorporated an e-mail system for exchange of current information.  It has become the campus' primary mechanism for exchange and dissemination of technical information in molecular biology.  Faculty and students of this group hold monthly meetings to update the information.     

Nucleic Acids Super Group:  The Nucleic Acids Super Group comprises several labs in Biochemistry, Pathology, and Microbiology & Molecular Genetics with an interest in the structure and function of nucleic acids that meet in a relatively informal setting on the second Monday of each month.  At each meeting, one lab presents their current work in one or two talks, given by the PI, postdocs, or students.

VLC Research in Progress:  This seminar series is for all members of the lung biology community.  It also includes our visiting professors.  Topics that are both clinical and basic are covered.

 Mentoring Plan: predoctoral students 

The graduate program in CMB has placed a special emphasis on mentoring from the first day.  As soon as applicants accept offers of matriculation, they are assigned both a faculty and student mentor.  They will remain with the applicant until they complete their first year and enter a laboratory.  In addition to the requirements presented by the training grant, each student is expected to fulfill all the responsibilities associated with the individual graduate program, including course requirements, oral and written presentations, and attendance at Departmental activities such as seminars and retreats.  The thesis advisor, who must be an active member of the training grant, is the primary mentor for each student, with a thesis studies committee providing the scientific expertise for evaluating research direction and progress.  Thesis studies committees for all Program trainees will be required to meet annually and must consist of at least one other member of the training grant faculty. 

 

The Program Director of the CMB Graduate Program and faculty assist in advising the student regarding to course selections, thesis research, and career development.  For students on the training grant, advice concerning career development is pursued through the following mechanisms. 

 

1)  Upon enrollment on the training grant, students meet with the Program Director and Executive Committee for an interview to discuss their thesis research, composition of their thesis studies committee, formal course schedule, and long term career goals.  Twice each year thereafter (or when required) individual trainees meet with the Program Director and Executive Committee to review their academic progress, research results, and relationship with their advisor and studies committee.  Special needs for individual trainees (i.e. laboratory training at other sites, advanced technical courses offered by institutions such as Cold Spring Harbor Laboratories , etc.) are identified and discussed at this time.

 

2)  Students will be required to attend two of the three seminar series. Many of the speakers at these series are external.  Students are reminded of the schedule each week by e-mail and poster announcements. Student groups commonly entertain external speakers for lunch, both to explore the scientific interests of the speaker and to discuss student training options.  On several occasions lunch meetings with speakers have resulted in postdoctoral opportunities for trainees.  A separate weekly seminar series in the CMB program is composed nearly entirely of internal student speakers.  Beginning at the end of their second year, all CMB students and trainees of this Program are required to present an annual research progress report). This will help the student to develop necessary presentation skills.  Postdoctoral fellows in the VLC laboratories also present.  We have also begun to invite 2-3 alumni of the CMB program each year to return to campus to present their research.

 

3) Students will be asked to prepare a mock NRSA research grant proposal describing their thesis project.  The grant proposals ensure that students are familiar with the background literature and technical information concerning their project, and have devised a suitable strategy for pursuit of their doctoral research project. Each year in June, trainees will present a progress report to Program faculty and other trainees for which they will receive a written critique summarizing the groups’ comments.  Finally, as students approach completion of their thesis research, the advisor, studies committee, and Program Director all assist in identification of laboratories suitable for postdoctoral training.  Together these activities ensure each student is monitored frequently in regard to academic performance and research progress.

 

4) The Training Program will require students to attend two national scientific meetings in order to present their research results and meet others in their field.  Students returning from meetings will present summaries. 

 

Postdoctoral Training

Postdoctoral training will be, by necessity, more of a custom-built program.  As a minimum, postdoctoral trainees will be required to attend seminars and retreats.  Workshop attendance is optional but encouraged.  In some cases, if appropriate, postdoctoral fellows will participate as presenters in these workshops if they possess the necessary skills.  As an example, the basic scientists asked for seminars covering clinical topics so we asked the PCCM fellows to present.  These talks were well received. The most critical thing is to assess the postdoctoral trainee’s needs and short-comings at the beginning of the program so that a focused plan to fulfill the needs of the trainee is put in place.  As an example, Matt Poynter, PhD was, until last year, a postdoctoral fellow with Yvonne Janssen-Heininger.  Matt came to UVM well-trained so his experience here was limited to seminar and retreat attendance, research and workshop attendance.  He did all these things enthusiastically and with a great deal of active participation.  This has lead to his being awarded a NIH-TIPS grant and an offer to stay on as faculty at UVM.  On the other end is Gil Allen MD.  Gil entered our PCCM clinical fellowship with plans to go into private practice.   However, once he arrived in the laboratory and discovered research he became dedicated to an academic career.  He, too, attended seminars, retreats and workshops but will still need to expand his knowledge and research skills.  In his KO8 application he proposes to take Cell and Molecular Biology 301 (Fall 2003), Biostatistics 201, Ethics in Research, Sterology workshop, Lung Pathology (4 days workshop offered by ACCP), Genetic manipulation of Mice and the VLC Grantsmanship workshop (summer 2003). We also determined that Gil needed to gain outside expertise in in vivo microscopy so this week he is in Syracuse to collaborate with Gary Nieman at Upstate Medical University to obtain these skills.  These examples illustrate the customization of our training efforts and our commitment to giving or obtaining the best raining for our trainees.

 

Mentoring Plan:  Postdoctoral trainees

As can be appreciated, mentoring is an important activity of the VLC, the PCCM unit and the CMB graduate programs. We take our responsibilities as mentors seriously, so it is a critical focus of both our training programs and our junior faculty activities.  (As an example, at our recent site visit from the CF foundation, one of the site visitors commented to one of our junior faculty, Laurie Whittaker, that there was clear and apparent evidence of involvement and senior mentoring now occurring at UVM.

Selection of mentors. The process differs somewhat for the predoctoral versus the postdoctoral prospective trainees.  ­­­­­­ Predoctoral students in the CMB program do laboratory rotations of three-four one-month rotations which are aimed at identifying a mentor and lab.  Some students come specifically to work with an individual that they have previously identified.  For the postdoctoral trainees, the PhD fellows typically identify mentors in the traditional fashion by contacts at meetings of similar venues and by calls, email or letter.  Suitable candidates are invited to visit Burlington, give a seminar and interview with at least 6 faculty.  In the case of the MD postdoctoral candidate, they are encouraged to visit and interview faculty, to attend meetings and then to identify a lab and mentor.  In the recent case of Scott Wagers MD, he had sought Dr. Irvin out while he was in Denver where he attended lab meetings and met the fellows and technicians to help formulate his decision.  Prior to being placed on the training grant, the executive committee will review the match of trainee to mentor(s), the research plan, career goals and educational plan as we are currently doing to insure a good match and likelihood for success.  It appears that to date this process is working very well for all parties.

 

Responsibilities.  Based on recent NHLBI recommendations (8, 12), we have developed formal delineation of responsibilities for both pre and post doctoral trainees and mentors. In addition, as described above, we have instituted a formal evaluation of mentors and trainees and assess their progress in both oral and written formats. The executive committee is responsible for these reviews and at appropriate points (years 2-3 and again in years 4-5) converge with the external review committee to review all aspects of the progress of this training program.

 

Use of multiple mentors has been an operating principle of these programs since its inception. As noted earlier, trainees with more junior primary mentors are linked with senior secondary mentors. This allows the junior mentor to benefit from the experience of his/her more senior colleague. One of the challenges for the postgraduate trainee is learning to balance the various parts of an academic career:  research, teaching, administration and, for the MD trainees, clinical medicine.  All fellows in the PCCM are assigned a faculty mentor on their first day of fellowship.  One of the responsibilities of this mentor is to help the fellow learn to move between the clinical and research arenas and to serve as a liaison between those two environments.  For example, during their second and third years of fellowship the fellows have 8 months devoted to clinical rotations and 16 months devoted to research.  In collaboration with the research mentor and the research committee, it is the responsibility of the fellow's overall mentor to be certain that the research time is protected from clinical responsibilities, and that everyone involved in the fellow's training understands the demands of the clinical service during the other 8 months.   Faculty mentors adhere to the following principles and practices:

 

1.      Teaching an understanding of research questions in the context of previous history, ideas and contributions to   the field;

  1. Teaching a critical approach to research questions and data analysis;
  2. Teaching selection, advantages and limitations of research methods;
  3. Involvement of the Steering Committee in review of research plans and trainee  progress;
  4. Frequent, scheduled meetings with trainees (including secondary mentors) for detailed discussions of research progress and plans, ideally weekly but not less than bi-weekly, with ready accessibility at other times as needed;
  5. Assistance with oral presentation of research data and writing of research communications

      and grant proposals in a way that fosters development of independent skills in these areas;

  1. Clear delineation of authorship of publications;
  2. An annual oral and written assessment of the trainee's progress, including specific strengths and weaknesses, and discussion of long-term professional goals;
  3. A commitment to assist the trainee with long-term career planning and development, including identification of appropriate "next steps" and introductions to scientists at other institutions.

 

Entering trainees are made aware that their mentors have agreed to these principles.

Correspondingly, entering trainees are acquainted with their responsibilities in a mentoring relationship, including:

 

  1. An understanding that success will require consistent dedication and taking of responsibility for their   progress, as well as a willingness to seek help whenever needed from their mentors; 
  2. An understanding that modern science requires that they function and behave as part of a collegial,  collaborative investigative “team", with respect the staff, other trainees and faculty;
  3. Attendance at scheduled lab meetings, seminars and evaluation sessions;
  4. Discussion with mentors before undertaking new initiatives and/or collaborations
  5. A thorough understanding of ethical guidelines and principles as well as the public trust

 underlying research activities.

  1. Attendance at UVM Orientation and Information Programs, which include a consideration of interactions with staff and faculty.

 

There are some additional institutional activities and policies that support mentoring. The seminar series on responsible conduct of research described below (which receives institutional support) includes significant material on responsibilities and ethical aspects of research, including mentor-mentee relationships. We also provide a formal workshop on mentoring for mentors and trainees. In addition, participating departments receive formula-driven funding based on the indirect costs they generate, a portion of which is dedicated to fund time involved in teaching activities related to the research projects that generate these funds. Thus, a portion of faculty salary funds mentoring activities.

 

Training will be provided or made available in current, modern, state-of-the art technologies to include cell-imaging e.g. confocal microscopy), in vivo multiphoton vital microscopy, advanced physiological measurements and creation of transgenic animals.  The College of Medicine is currently setting up a microarray facility and has recently received a NCRR instrumentation grant for a MALDI-MS for protenomic studies.  Bioinformatics are still a perceived need.  Where technology is inadequate or not available, trainees will attend courses or be sent to institutions where such training can be obtained.

 

One of the finest aspects of the research environment at UVM is the highly collegial atmosphere.  Everyone is genuinely interested in helping each other and willing to collaborate.  This is a recurring point of praise that is raised by both faculty and students and is clearly one of the distinguishing factors of UVM. Students are also very pleased with the individual attention that they receive, as faculty are very concerned with their students’ success.  In fact, in a recent survey of graduate students at UVM, those in the CMB Program stated that: 1) 86% strongly agreed with the statement that faculty advisors effectively support the professional development of the student; 2) 90% strongly agreed with the statement that the program provided challenging research opportunities.

 

 

1) Bresnitz, EA Epidemiology of advanced lung diseases in the United States. Clinics in Chest Medicine 18:427-433 1997

2) Vermont Department of Health Statistics 1998.

3) NHLBI National Heart, Lung and Blood Institute Strategic Plan 1999. www.nih.gov/nhlbi

 

4) Chabner BF, Borai AL, Multani Translational Research: walking the bridge between idea and cure. Ann Int Med. 343: 4211-4216, 1998

 

5) Gelijns AC, Rosenberg N, Moskowitz AJ. Capturing the unexpected bebfits of medical research N.Engl J. Med 339:693-698, 1998.

 

6) Irvin CG, Berend N, Henson PM.  Airways hyperreactivity and inflammation produced by aerosolization of human C5A des arg.  Am Rev Respir Dis 134:777-783, 1986.

 

7) Murphy KR, Wilson MC, Irvin CG, Glezen LS, Marsh WR, Haslett C, Henson PM.  The requirement for polymorphonuclear leukocytes in the late asthmatic response and heightened airways reactivity in an animal model.  Am Rev Respir Dis 134:62-68, 1986

8) Gottesman MM. A guide to training and mentoring in the intramural research program at NIH National Institutes of Health office of the Director, 2002 

 

9) Selby, CC ed. Women is Science and Engineering Ann NY Acad Sci 869:7-15, 1999

 

10)Bickel j et al. Increasing women’s leadership in academic medicine:  a report of the AAMC project  implementation committee Acad Med 77:1043-1061, 2002

 

11)Chesler N, Chesler M  Dilemmas in the mentoring of faculty women in engineering; The heroic journey vs the caring community.  Abst ( see Appendix 1) 2000

 

12)Mentorship Guide  National Academy of Science  www.nap.edu