DEPARTMENT OF MEDICINE

PULMONARY, CRITICAL CARE AND SLEEP MEDICINE RESEARCH

Research Programs in Pulmonary, Critical Care and Sleep Medicine

Overview

One of the primary missions of the Pulmonary, Critical Care and Sleep Medicine Division is the discovery and dissemination of new knowledge to the medical and research community. Our faculty are actively engaged in research programs that span the full gamut of medical research form clinical to translational to basic sciences. Every member of the division is involved in some aspect of our research mission. The current research portfolio consists of federally funded individual investigator initiated projects, mentored career development awards, multi-investigator grants, a training grant, foundation awards, federally funded clinical research projects and industry sponsored study protocols. Our current research portfolio consists of a multi-investigator cluster grant (4 RO1s), 8 RO1/VA Merit Review/Program Projects, 4 VA or NIH funded mentored career development awards, an R21, 3 foundation research awards, an NIH funded training grant, 2 NIH funded clinical trial network grants (ARDS Network, Long-term Oxygen Therapy Trial), and 15 industry sponsored protocols.

Research Areas

The division has 5 major research themes: Control of Breathing, Lung Injury and Inflammation, Pulmonary Epithelial Cell Biology, Clinical Epidemiology, and Clinical Research:

• 1.) Control of Breathing. The control of breathing research group has been a major focus of the division for over 20 years. Currently 6 faculty members have active research programs in this area with independent, but overlapping areas of interest and strong collaboration as seen through their joint publication record. Kingman Strohl’s (M.D.) (Professor) research is in sleep disordered breathing. He is currently investigating the genetic basis of differences in rat ventilatory patterns. He has just completed a comprehensive QTL analysis looking at two informative rat strains with varying respiratory patterns. With this information, he is now embarking on a high density mapping project of informative areas identified in the rat genome. Dale Feng’s (M.D., Ph.D.) (Assistant Professor) expertise is in the development of sleep patterns with age, and small animal neural recording. His work seeks to explain the behavioral and biochemical basis of sleep/wake cycle ontogeny. He also has significant skills in his ability to study continuous, long term, neural recordings in small animals in their natural state and environment. Ted Dick’s (Ph.D). (Associate Professor) research is in pontine control of ventilation. His recent work involves the recording of multiple neurons from entire neural regions of the pons instead of single cells to identify their connections and cross-talk, and develop computer models of these interactions to understand the pontine diaphragmatic pacemaker. There is significant collaboration and complementation between Drs. Dick and Strohl with recent studies on the effect of CPAP on pontine regulation of breathing and cardiac function. Dr. Dick is a thought leader in this area, and recently was awarded a NIH funded cluster grant (4 inter-related RO1s) strengthening collaborations among this research group and important national and international collaborators. Eric van Lunteren’s (M.D.) (Professor) research program is focused on the respiratory neuromuscular system, including the central neural control of breathing, the regulation of neuromuscular transmission, and the biology and pathophysiology of skeletal muscles with an emphasis on the diaphragm. His recent work is examining the role of K+ channels in respiratory muscle contractile and electrophysiological properties and examining plasticity in the K+ channel regulation of muscle contraction by testing animal models of exercise and disease. Dr. van Lunteren collaborates closely with Dr. Dick as shown by their joint publication record. Frank Jacono, M.D. (Assistant Professor) was a fellow in the Division’s Pulmonary and Critical Care Fellowship program. During the research component of his fellowship and while a junior faculty member, he worked on carotid body oxygen sensing with Nanduri Prabhakar, Ph.D., Vice Chair of Physiology and Biophysics and an international expert in carotid body oxygen sensing. His current projects revolve around understanding respiratory variability, its mechanism, and its prognostic meaning. Dr. Jacono currently holds a VA Advanced Career Development Award, a mentored career development award for developing physician-scientists. David Baekey, Ph.D., (Instructor) is the newest addition to this research group. Dr Baekey completed his Ph.D. at the University of South Florida, came to Case for post-doctoral work with Dr. Dick, and then joined the Division faculty. His research involves the neural control of respiratory and cardiovascular control focused on the coordination between respiration and sympathetic outflow patterns during and after hypoxic challenges. The goal of his studies is to generate a quantitative, mathematical model that describes the generation and control of breathing and to simulate breathing using both cellular and network properties of neurons involved in breathing.

• 2.) Pulmonary Epithelial Cell Biology/Lung Injury – The pulmonary epithelial cell biology research group consists of Jeffrey A. Kern, M.D. (Professor), Jihane Faress, M.D. (Assistant Professor) and Jay Finigan, M.D. (Assistant Professor). Dr. Kern is known for his work in membrane bound receptor tyrosine kinases, specifically in the EGFR growth factor receptor family. The central hypothesis being explored is that activation of this receptor family and downstream second messenger systems in the pulmonary epithelium regulates epithelial cell proliferation and differentiation. Dr. Kern has taken a biochemical approach to understand the receptor in his prior work, and more recently has moved into in vivo systems. Through the development of transgenic mice that overexpress the ligand, or express a dominant negative receptor, he is studying the role of this receptor/ligand system in vivo. These studies include model systems of normal epithelial cell proliferation and differentiation (lung development), abnormal growth (lung cancer), and wound repair (acute lung injury). Dr. Faress studies also revolve around the pulmonary epithelium. Her interest is in the modulation of receptor signaling by the inflammatory environment. She has recently described novel interactions between inflammatory cytokine receptors and growth factor receptors that bring together what were previously though to be unrelated receptor signaling pathways into a unified model. Her in vivo studies extend this model into the development and testing of new therapeutic drugs and strategies to modify recovery from lung injury and prevent fibrosis. Jay Finigan’s research seeks to understand the signaling mechanisms activated by activated protein C (APC, XygrisÒ). This has become an important molecule in medicine as APC decreases mortality of patients with sepsis, but how it works is not clear. Dr. Finigan hypothesizes that APC, through its receptor on endothelial cells induces receptor dependent cytoskeletal reorganization, thereby reducing endothelial permeability in vitroand improving patient survival. He has extended this concept to ventilator associated lung injury, where the same permeability problem occurs, and postulated that APC might serve as a novel therapeutic agent in ventilator associated lung injury in vivo. Dr. Finigan has published novel work in the area confirming that APC enhances pulmonary endothelial barrier function in vitro via alterations in the endothelial cytoskeleton, and reduces vascular permeability in a murine model of ventilator associated lung injury. Dr. Finigan recently received a NIH K08 mentored career development award. Acute Lung Injury is also being explored through clinical trial networks as a member of the NIH ARDS Network (Dr. Hejal, PI).

Within the pulmonary epithelial cell biology research area there also is a strong interest in lung cancer. A multi-disciplinary group consisting of investigators in the Hematology and Oncology Division as well as the Pulmonary, Critical Care and Sleep Medicine Division are focused on the EGFR family and its downstream signaling to further understand transformation events within the pulmonary epithelium, as well as design novel therapeutics and therapeutic strategies for lung cancer.

• 3.) Immunology/Inflammation – Currently Richard Silver, M.D., (Associate Professor), is actively working in pulmonary immunology and inflammation. Dr. Silver’s research program is based around the study of human immunity to M. tuberculosis. He has developed a novel antigen stimulation system using direct bronchoscopic instillation of PPD into the lung, followed by bronchoalveolar lavage cell recovery from the “immunized” area, as well as the contralateral “non-immunized” lung. The development of this novel approach is yielding important information about how protective immune responses are mobilized to the lung in response to inhaled pathogens. In addition, organ-specific responses are being studied as the preliminary evaluation of the efficacy of tuberculosis vaccines. As an extension of Dr. Silver’s interest in innate immunity he is also studying the granulomatous inflammation that develops during tuberculosis infections and sarcoidosis. Studying response of individuals with sarcoidosis as well as in mouse models, he is exploring the hypothesis that the host’s abnormal immune response to a number of different pathogens results in granulomatous inflammation.

• 4.) Clinical Epidemiology - Susan Redline, M.D., M.P.H. (Professor), is an internationally known investigator with a multifaceted research program that has a primary focus on the study of sleep disorders. She heads a Sleep-Heart Health Center that has pioneered approaches for collecting, processing, and analyzing complex polysomnography data and assisted in protocol development, centralized scoring, and quality control for sleep studies to better understand cardiovascular morbidity occurring with sleep apnea. Outcomes of sleep disorders in adolescents are a special interest of her research group. She is determining the prevalence, risk factors, and associated co-morbidity (neurocognitive, behavioral, and metabolic) of sleep disorders in children, ages 13 to 16 years to determine the rate or progression, and determinants of progression, of sleep disordered breathing from middle childhood through adolescence. Dr Redline also directs the UHCMC Sleep Program and the Sleep section within the Division. Rena Mehra, M.D. (Assistant Professor) completed a Sleep, Neurobiology and Epidemiology research fellowship after her Pulmonary and Critical Care Fellowship, mentored by Drs. Redline and Strohl. During the fellowship she completed a Masters of Science in Clinical Investigation. Her current hypothesis explores specific pathways of oxidative stress as mediators linking sleep-disordered breathing and cardiovascular disease. The understanding of the inter-relationship of oxidative stress and sleep-disordered-breathing, and its impact on cardiac disease may allow identification of individuals at risk for sleep-related co-morbidity, help target drug therapy in high-risk individuals, and identify intermediate outcomes to use in subsequent observational and interventional studies. Dr. Mehra is the recipient of a NIH K23 mentored career development award. Sanjay Patel, M.D., M.S. (Assistant Professor), research interests are focused on the genetic etiology of obstructive sleep apnea, obesity, and the attendant risk factors of these disorders. Dr. Patel has made significant contributions to the field correlating leptin levels and adiposity, and begun to quantify the shared genetic basis for sleep apnea and obesity, demonstrating that approximately 50% of the genes for sleep apnea are likely to be unique from those for obesity. One of his specific goals is to define the genetic associations between common sleep and metabolic disorders such as diabetes and obesity. He is a key member of the CARe (Candidate Gene Association Resource) consortium, a NHLBI funded project that aims to identify genetic variants for common heart, lung, blood and sleep disorders, and has co-led the first CARe proposal to conduct a genome wide association study of sleep apnea. Dr. Patel holds a NIH K08 mentored career development award.

• 5.) Clinical Research: Clinical research within the division is focused on pulmonary artery hypertension (PAH), acute lung injury and hypoxemia. Our PAH program is under the direction of Robert Schilz, D.O., Ph.D, (Associate Professor). Dr. Schilz has a national reputation in PAH and is involved in the design and implementation of many new PAH drug trials. He has developed/participated in multiple clinical trials regarding new therapies for PAH. Currently, nine clinical trials are open and accruing patients with pulmonary hypertension below are a few:
• a.) United Therapuetics Corporation: TDE PH-301 – A 16 week comparison study of the efficacy and safety of oral UT-15C sustained release tabs in combination with an endothelin receptor antagonist and/or a phosphodiasterase-5 inhibitor in subjects with pulmonary hypertension.
• b.) MyogenInc: AMB-320/321-E – a long term study of Abrisentan In Pulmonary Arterial Hypertension Subjects having completed AMB320 or AMB321.

Additionally, our clinical trails group is active in five other trails dealing in various aspects of Pulmonary Diseases.

Dr. Schilz is also conducting clinical research in Diaphragm Paralysis in collaboration with Ray Onders, M.D., Department of Surgery. This research group is a pioneer in the application of new technology to this problem with surgical mapping of the diaphragms response to stimulus and insertion of diaphragm sensors/wires for pacing.

Clinical Research in Acute Lung Injury is under the direction of Dr Rana Hejal (Associate Professor). Our intensive care unit (Dr. Hejal, Medical Director) is an ARDS Network site and we actively participate in all ARDS Network clinical trial development, design, implementation and patient accrual.

Clinical research in hypoxemia is progressing as part of the NIH funded Long-term Oxygen Therapy Trial. Our division is part of a city wide consortium participating in the trial with Mariana Petrozzi, M.D. (Assistant Professor), Kingman Strohl M.D. (Professor) and Jeffrey Kern, M.D. (Professor ) participating in the trial.

Our clinical trial program is supported by on outstanding Clinical Trials Research Unit that is dedicated to supporting the division from study identification, project development, IRB submission and tracking, regulatory document preparation, subject identification, and data collection and reporting.

Summary

The Pulmonary, Critical Care and Sleep Medicine Division has active research programs spanning clinical, translational and basic investigation. The entire division participates in its research mission, and its internationally known faculty of physician-investigators are leaders in their field. The success of the Division’s research efforts can be seen in its outstanding mentoring of fellows to faculty positions, supporting junior faculty to independent research careers, and the international reputation of its senior investigators. The impact of the Division’s research programs can be seen in its outstanding publication record and grant support. The Division continues to grow its research portfolio and is always looking to increase its cadre of physician investigators.