Training Program in Pulmonary Diseases and Critical Care Medicine

University of North Carolina School of Medicine

Division of Pulmonary and Critical Care Medicine
Department of Medicine
Chapel Hill, North Carolina

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Detailed Program Brochure

OBJECTIVE

The objective of this program is to help post-MD trainees develop a scholarly approach to pulmonary medicine, critical care medicine and lung biology enabling them to pursue a variety of career options, including academic medicine. To meet this objective, we offer an accredited three year combined program in Pulmonary Diseases and Critical Care Medicine that qualifies trainees for certification in both subspecialties. The latter years of the training program are intended to provide an in-depth experience with clinical and/or basic science investigation. Trainees who desire to obtain a substantial experience in research will need a particularly intense effort and may require an additional period of research training.

CLINICAL FACILITIES

The School of Medicine has a four-year curriculum with ~ 160 students per class. Other major components of the Health Affairs complex include the Schools of Dentistry, Public Health, Pharmacy, and Nursing, as well as a number of Institutes and Centers.

The clinical programs of the Department of Medicine are based in the UNC Hospitals, which serves as the principal teaching institution for the University of North Carolina School of Medicine, as the community hospital for the town of Chapel Hill and its environs, and as a state-wide referral center. UNC Hospitals is a Level I Trauma Center with active lung, heart-lung, heart, renal, pancreas, liver and bone marrow transplant programs. The hospital has 660 beds of which 107 are devoted to intensive care. The three-year residency training program in internal medicine includes approximately 70 residents and 100 full-time faculty who represent all the subspecialties of internal medicine. There is a substantial outreach program which provides medical students and post-MD trainees opportunities in a number of hospitals and practices throughout the state of North Carolina.

The UNC Hospitals Pulmonary Function Laboratory (PFL) is equipped for all types of applied pulmonary physiologic studies including progressive and steady state exercise testing using a computerized data acquisition system, lung mechanics, and bronchoprovocation challenges. A fully-equipped bronchoscopy suite (including video display and recording) is located near the pulmonary function laboratory and the pulmonary in-patient service. Patients with sleep-related breathing disorders are studied in the evenings by full-time polysomnography technicians in a laboratory dedicated to sleep studies. An outpatient PFL is located within the Pulmonary module at the Ambulatory Care Center.

CLINICAL ACTIVITIES        

The Clinical Services of the Division are under the overall direction of Dr. Michael Knowles. These include an inpatient pulmonary service, a combined respiratory and medical ICU, a pulmonary consultation service, and a medical lung transplantation service. Comprehensive pulmonary and critical care medicine training and services are provided, as well as special expertise in 1) CF and airways diseases, 2) Sleep-related respiratory disorders, 3) Thoracic oncology, 4) Pulmonary hypertension, 5) Lung transplantation, and 6) Lung volume-reduction surgery.

The inpatient service admits 60-90 patients per month and is staffed by interns, residents, third-year students, and an attending (pulmonary medicine) physician. Patients are admitted through a variety of channels including (i) direct referrals, (ii) the pulmonary clinics, (iii) the emergency room, and (iv) transfers from the ICU.

The Respiratory Intensive Care Unit (RICU) and the adjacent Medical ICU (MICU) admit about 125 patients per month and are staffed by three resident-intern teams. A Pulmonary/Critical Care attending physician and a first year fellow are assigned to the RICU and MICU each month of the year. Senior fellows may serve in a supervisory capacity with faculty backup in the ICU. The fellow and the ICU attending are also responsible for all pulmonary consultations requested by other intensive care units in the hospital. Dr. James Yankaskas is the director of critical care services for the Department of Medicine.

The Consultation service evaluates approximately 60 out- and in-patients each month and is staffed by students, a medical resident, a pulmonary fellow and a pulmonary attending. This service performs most pleural biopsies and bronchoscopies and interprets all pulmonary function tests.

The medical lung transplantation service is directed by Dr. Peadar Noone. Fellows rotating on this service provide pre-transplantation evaluation and post-op care for lung transplantation patients.

The Division operates several outpatient pulmonary clinics. A weekly Fellows' clinic is supervised by Divisional Faculty. Fellows may also participate in the airways disease/allergy clinic under the direction of Drs. James Donohue and David Henke and in the Multidisciplinary Thoracic Oncology clinic directed by Dr. M. Patricia Rivera. Adult cystic fibrosis patients are followed by Fellows under the supervision of Drs. Michael Knowles, James Yankaskas, Scott Donaldson and Raymond Coakley.


RESEARCH ACTIVITIES        

The areas of lung biology and physiology under current study are described below. A major strength of the faculty has been its ability to take ideas from basic science investigation into clinical studies at the bedside. The faculty and trainees have an active record of publication and presentations at national meetings.

I. Epithelial pathogenesis of airways diseases: This area of research includes: (a) cystic fibrosis transmembrane regulator (CFTR) protein function: These studies focus on structure/function relationships between CFTR and cAMP-regulated Cl- channel function utilizing an interdisciplinary approach consisting of molecular biology, biophysics, and mouse models. In parallel, the regulatory effects of CFTR on the activities of other channels, including the outwardly rectifying Cl- channel are under investigation; (b) Regulation of Na+ transport in airway epithelia: Interactions between Na+ channel (ENaC) subunits and CFTR are being explored in the normal control of Na+ transport in airway epithelium and the pathogenesis of CF. These studies employ a variety of approaches including heterologous cell systems, mutagenesis, and transgenic (conventional and knockout) mice; (c) The relationship of CFTR dysfunction to airways infection: A variety of approaches, focusing on measuring the effects of airway surface liquid composition on bacterial killing and adherence are underway; (d) Identification of genes that modify the severity of the CF phenotype in the lung: Whereas patients who are homozygous for the D F508 mutation routinely have pancreatic insufficiency (more than 95% of the pancreas is destroyed), patients with this genotype have a wide variation in loss of pulmonary function. This observation raises the possibility that there are modifying genes that can buffer the severity of the D F508 genotype in the lung as compared to pancreas. We are currently exploring components of the "alternative Cl- channel" (Cl-a) pathway as one set of candidate genes, both by cloning the Cl-a gene and by evaluation of the ATP/UTP-dependent Cl- secretory system, in the airways of these patients; (e) Cystic fibrosis of genotype/phenotype correlations: relationships between specific genotypes and sweat ductal and airway epithelial dysfunction are being measured. Investigators focused on epithelial pathogenesis include Drs. Boucher, Donaldson, Gabriel, Grubb, Knowles, Koller, Noone, Olsen, and Stutts; (f) Pathogenesis and a treatment of primary ciliary dyskinesia (PCD): genes responsible for ciliary structural and functional properties are being identified and characterized, while pharmacological means to augment cough clearance in PCD patients are being developed and tested in vivo. Investigators include Drs. Ostrowski, Boucher, Carson, Knowles, Noon, Randell, Sannuti, and Yankaskas.

II. Gene therapy: A major effort has been devoted to development of gene therapy technologies. The three goals that describe the efforts of the UNC Gene Therapy and the Cystic Fibrosis/Pulmonary Research & Treatment Center efforts are as follows: 1) development of more efficient and safe gene transfer vectors; 2) application of vectors to in vitro and in vivo biological systems; and 3) application of vector systems to human clinical trials. Under the leadership of Drs. Boucher, Grubb, Koller, Randell, Samulski, & Yankaskas, these activities are housed in the Applications Laboratory in Thurston-Bowles Building that utilizes both cell culture and animal models for these studies. A basic science vector core has been established to promote these studies. Under the leadership of Drs. Knowles and colleagues, a clinical trial of Adenovirus Gene Transfer to the nasal epithelium was conducted in the UNC Hospitals General Clinical Research Center, which has been renovated for production of clinical grade (GMP) vectors and to provide rooms specially configured to house patients undergoing gene therapy. To date our efforts have focused on gene therapy approaches to CF and lung cancer.

III. Animal models: Under the direction of Dr. Beverly Koller, a major effort has been devoted to exploring the function of genes in intact mammalian systems. Two systems (conventional transgenic mice, and "knockout" mice) have been utilized and major facilities developed to explore the addition and deletion of genes in intact mammalian systems. A series of transgenic and homologous recombination (knockout) mice have been generated by the UNC faculty. The best-known is the cystic fibrosis mouse, which was generated by homologous recombination of a disrupted exon 10 of the murine CF gene (located on chromosome 6). This animal has been extremely useful for the identification of the alternative Cl- channel (Cl-a) as well as rapid testing of gene therapy vectors. The CF mouse model has been recently modified to selectively express the human CFTR cDNA in the gut epithelium to extend the lifespan of the animals and consequently the number of animals available for pulmonary research. Finally, this model has been used for structure/function studies by expressing the mutant CFTR cDNAs in the intestine of this animal.

A major effort has also been voted to exploring the biology of the purinoceptor (P2Y2) system in mice. Important questions with regarding the relevance of the purinoceptors in organ-level physiology have been addressed using the deletion approach, i.e., "knockout" of the P2Y2 receptor. These studies are complemented by a series of approaches using transgenic models to identify the regulatory elements of the purinoceptor genes.

The use of mouse models to study pulmonary inflammation has been enabled by the recent generation of a high-affinity IgE receptor knockout mouse, a 5-lipoxygenase knockout, and a LTA4 hydrolase knockout animal. The efforts to generate molecularly modified mice have been complemented by a large effort to measure the pulmonary phenotype in these mice, including bioelectric properties, morphometry, and pulmonary function.

IV. Developing lung: Two major areas of lung development are under investigation. Under the leadership of Drs. Barker and Gatzy, the epithelial ion transport activities that are responsible for the transition of the fetal lung from a liquid-filled to a gas-filled organ are being studied. The level of investigation at present relates to the molecular triggers that regulate gene expression for Na+, CFTR, and Cl-a channels. This area of investigation has recently focused on ENaC knockout mouse models. These studies are paralleled by studies of Drs. Leigh, Noah, and Retsch-Bogart on the response of airway epithelial tissues in the neonate to injury. These studies have also been complemented by the studies of Dr. Scott Randell, who is studying progenitor/progeny relationships in both neonatal and adult airways.

V. Purinoceptors: In the last six years, investigators at UNC have recognized that extracellular triphosphate nucleotides (ATP/UTP) have profound actions on the functions of the surface airway epithelial cells. These studies have reflected the activities of a large number of investigators, including Drs. Boucher, Davis, Donaldson, Gabriel, Grubb, Harden, Knowles, Paradiso, and Stutts, have identified major actions of ATP/UTP in (a) activating an apical membrane alternative Cl- conductance and an apical K+ conductance, which stimulate net salt and water secretion; (b) inducing goblet cells to initiate mucin granule discharge; and (c) stimulating ciliated cells to increase ciliary beat frequency. Major efforts are underway to isolate and clone P2 receptors that transduce these effects and initial efforts have resulted in the cloning of a human ATP/UTP receptor, termed the P2Y2 receptor. This initial success has spurred structure/function studies on this class of receptors and cDNA library screening for novel members of this class of receptors. As discussed above, these concepts have led to studies designed to elucidate the organ-level biology of these receptors, including studies in overexpressing and knockout mice. Finally, these studies have triggered a major clinical effort to explore the potential therapeutic effects of aerosolized ATP/UTP.

VI. Respiratory Toxicology (P. Bromberg and others)

A. Organizational Units

• UNC Center for Environmental Medicine and Lung Biology (CEMLB)(P. Bromberg, Director)

• U.S. Environmental Protection Agency Human Studies Division (H. Koren, Director)

• Interactions with:

B.  CEMLB Investigators

P. Bromberg, M.D., N. Alexis, Ph.D., W. Bennett, Ph.D., B. Boehlecke, M.D., J. Carson, Ph.D., W. Cascio, M.D., A. Collier, M.D., L. Graves, Ph.D. (Dept. Pharmacology), I. Jaspers, Ph.D., M. Hazucha, M.D., Ph.D., S-C. Hu, Ph.D., T. Noah, M.D., D. Peden, M.D., W. Reed, Ph.D., W. E. Sanders, M.D., K. Zeman, Ph.D.

C. General Research Objectives

1. Determine mechanisms of effects of exposure of the human respiratory tract to inhaled chemicals and biologicals (volunteers and cultured human respiratory cells).

2. Characterize hypersusceptible individuals (e.g., pre-existing disease; genetic factors).

3. Modify airways function pharmacologically.

D. Facilities (on site)

• 65,000 net sq. ft. Research Building on UNC Medical Campus (just south of Thurston-Bowles Building) shared by US EPA Human Studies Division and UNC CEMLB.

• Specialized environmental exposure chambers for volunteers and for cultured cells.

• Subject examination/evaluation areas.

• Bronchoscopy suite.

• Sputum induction and analysis

• Preparation of radiolabelled and non-labelled particles
        Particle counters
        Gamma camera (Elscint)

• Small-volume inspiratory bolus capability.

• Human lung function testing.

• NO analysis

• Breath condensate collection and analysis

• Human non-invasive cardiac electrophysiology.

• Respiratory tissue morphology laboratory
(immunohistochemistry, TEM, SEM, video microscopy)

• Cell culture

• Molecular biology

• FAC analysis

• Immunoassays for cytokines

• Phosphorimager

E. Areas of active investigation

• Molecular biology and signal transduction of human airways epithelial responses to oxidants, metals, injury. -  Reed, Jaspers, Samet (EPA), Ghio (EPA), Devlin (EPA), Graves

• Epithelial injury and repair, differentiation. –   Reed, Jaspers, Carson, Collier, Noone (CF Center) and others in the CF Research Center and Pediatric Pulmonary SCOR group.

• Airways inflammation, infection and allergy related to inhaled agents. - Peden, Alexis, Noah, Becker (EPA), Arnold (Dental Research), Devlin (EPA)

• Dosimetry and clearance of inhaled particles, solutes, and reactive gases in healthy and diseased subjects. Modelling. Fluid mechanics. – Bennett, Hu, Zeman, Lay, Kim (EPA)

• Pharmacotherapy of impaired airways clearance. –   Bennett, Zeman, Knowles (CF Center)

• Mechanisms of action of inhaled pollutants on the heart. –   Sanders, Cascio, Bromberg and others

• Mechanism of effect of inhaled ozone. -   Bromberg, Hazucha, Hu, McDonnell (EPA)

• Genetic factors in susceptibility. - Samet (EPA), Bromberg, Devlin (EPA), Koren (EPA)

• Disease and susceptibility. – Peden, Hazucha, Sanders, Kehrl (EPA), Ghio (EPA), Huang (EPA), Devlin (EPA), Bromberg

F. Education and Enrichment

• Fellowship training in bench and/or clinical research

• CEMLB seminar/work-in-progress (monthly)

• CEMLB/EPA invited seminars

• Visiting Pulmonary Scholar Programs: Visiting Pulmonary Scholar Programs: Consortium of local pulmonary research groups (CEMLB, US EPA, NIEHS, Duke pulmonary division, NC State University School of Veterinary Medicine, Glaxo-Wellcome) organize and fund 2-day visits of six prominent pulmonary investigators each year, including joint dinner and research presentations. The 2006 - 2007 scholars include: Jay K. Kolls (Children's Hospital of Pittsburgh, Pittsburgh, PA,); Albert van der Vliet, PhD (University of Vermont, Burlington, VT); Craig Gerard, MD, PhD (Children's Hospital Boston, Boston, MA); Charles Irvin, PhD (University of Vermont, Burlington, VT); Peter Gehr, PhD (University of Gehr, Switzerland); and Zea Borok, MD (University of Southern California, Los Angeles, CA.)

G. Funding

• General Cooperative Agreement of CEMLB with US EPA

• Grants and Contracts to individual investigators

VII. Current Clinical Studies: Under the leadership of Drs. Knowles, Aris, Carson, and Donohue a major effort has been dedicated at UNC to clinical investigation. The significant interface is between basic scientists and clinical scientists.

List of current clinical studies

 

TEACHING CONFERENCES

The division and department provide a number of clinical and research conferences, some of which are listed below:

RESEARCH CONFERENCES:

TRAINING PROGRAM

First Year:

The first year is designed to give 6 months experience in clinical pulmonary disease and 6 months experience in critical care medicine. The training in pulmonary disease is obtained through the consultation service, the outpatient clinics, pulmonary function laboratory, and the pulmonary ward. Critical care experience is largely gained from rotations in the MICU/RICU and the lung transplantation service. Each fellow is encouraged to use applied physiology to gain a better understanding of disease processes and therapy and to perform in depth reading in order to gain special expertise. All fellows are expected to participate actively in patient care and teaching. In addition, they are required to gain special expertise in ventilator management, hemodynamic monitoring and other ICU procedures. They are also expected 1) to become a technical expert in pulmonary function test performance; 2) to become an expert in pulmonary function test interpretation; 3) to perform all bronchoscopies and other procedures on patients on their assigned services.

Second and third years:

The structure of the latter two years of the training program is tailored to the trainee's interests and plans. At least 6 months of the final two years of training must be devoted to full-time clinical training in addition to a one half day/week clinic to meet criteria for combined pulmonary and critical care certification. In general, all trainees are expected to undertake investigative project(s) related to pulmonary or critical care medicine under the guidance of one or more of the training program faculty. This research training involves developing a reasonable project, learning to perform the needed techniques, setting up specific experimental protocols with adequate controls, analyzing data, presenting the work in a coherent manner, and eventually writing manuscripts and grant applications. Trainees are also encouraged to take pertinent courses at the University with reimbursement of their expenses (e.g., Cell Biology; Molecular Biology Laboratory). Fellows who are serious about competitive academic careers may pursue a fourth year of research training. While such individuals may be asked to write a grant, performance of the fourth year is not contingent upon receipt of funding.

Fellows who choose not to pursue research training are still expected to contribute to clinical research studies and will have increased clinical responsibilities in their latter years of training.

STIPENDS
The training program stipends are supported by clinical income, a NHLBI research training grant, a Cystic Fibrosis Foundation training grant, and by funds from other organizations (ALA, Cystic Fibrosis Foundation, U.S. Environmental Protection Agency). Other benefits for fellows include three weeks annual vacation, use of a personal computer with modem and printer, library xerox privileges, and travel and lodging to one national meeting per year.

 

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