PULMONARY, CRITICAL CARE
AND SLEEP MEDICINE RESEARCH |
Overview
The Pulmonary, Critical Care and Sleep Medicine Division has
13 faculty members: 1 Ph.D., 2 M.D./D.O. Ph.D.s, and 10 M.D.s.
Three of the faculty members are involved in clinical care full
time (Drs. Hejal, Montenegro, Petrozzi). Two faculty members
are full time scientists (Drs. Dick, Feng). Eight faculty members
are physician scientists, in either clinical or basic research
areas. The current basic research faculty (Drs. Silver, Dick,
Kern, van Lunteren, Strohl, Jacono) have a research portfolio
consisting of 6 R01s, 4 VA Merit Reviews, 8 non-federal grants
and 1 training grant for a total yearly direct funding of $1,761,420.00
The clinical research program (Drs. Schilz, Mehra, Kern) has
a research portfolio of 5 industry sponsored open protocols
for a total up to date funding of $81,198.89.
Research Areas
The division has 4 major research themes: Control of Breathing,
Inflammation, Pulmonary Epithelial Cell Biology, Clinical Research
Control of Breathing
Dr. Neil Cherniack first established the control of breathing
research group while he was Pulmonary and Critical Care division
director. Though Dr. Cherniack left the division over 15 years
ago, this theme and the investigators in this area remain strong.
Currently 4 faculty members work in this research area and two
junior faculty members are developing. The investigators have
independent, but overlapping areas of interest with strong collaboration
as seen through their joint publication record. Dr. Kingman
Strohl’s (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 M.D., Ph.D. (Assistant Professor)
was recruited from Emory University for his interest in the
development of sleep patterns, and expertise in small animal
neural recording. His work adds a new emphasis on research to
explain sleep/wake cycle ontogeny and he has added new skills
in his ability to study neural recordings in a natural state.
There is significant collaboration between Drs. Strohl and Feng
with shared laboratory space, grant support and publications.
Dr. Ted Dick’s (Associate Professor) research is in pontine
control of ventilation. His recent work involves the recording
of neural regions instead of single cells in the pons to identify
connections and develop computer models of 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. Eric van Lunteren’s (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.
Two junior faculty are developing in this area. Frank Jacono,
M.D. was a fellow in the Division’s Pulmonary and Critical
Care Fellowship program. During the research component of his
fellowship and continuing while an Instructor, Nanduri Prabhakar,
Ph.D., Vice Chair of Physiology and Biophysics mentored him.
Dr. Prabhakar is an international expert in carotid body oxygen
sensing. Dr. Jacono is developing a research hypothesis around
carotid body sensing of signals other than oxygen. His current
project studies the regulation of carotid body signaling in
a lung injury model evaluating oxygen sensing, vagal feedback
and the systemic inflammatory response on ventilatory control.
Dr. Jacono successfully competed for an American Heart Association
fellowship award (2004-06) and will be applying for a NIH career
development award this spring.
Reena Mehra; M.D., M.S. is the second developing junior faculty person in this research area. Dr. Mehra finished a Pulmonary, Critical Care and Sleep Medicine Fellowship at the Cleveland Clinic Foundation and came to our division for a Sleep, Neurobiology and Epidemiology research 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. She is also investigating sleep-disordered breathing and nocturnal cardiac arrhythmia associations. Dr. Mehra has funding from an American Heart Association National Scientist Development grant (2004-2008), a T. Franklin Williams American College of Chest Physicians Associated Subspecialty Professors Geriatric Development Award (2005-2007), and has recently been notified of funding from the K12 Multidisciplinary Clinical Research Training Program.
Pulmonary Epithelial Cell Biology/Signaling
The pulmonary epithelial cell biology research area is led
by Jeffrey Kern, M.D. (Professor). Dr. Kern is known for his
work in membrane bound receptor tyrosine kinases, specifically
in the EGFR growth factor/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 understanding 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. Kern is also serving as the mentor for a Hematology/Oncology
junior faculty member (Afshin Dowlati, M.D., Assistant Professor)
working in his laboratory on tyrosine kinase signaling in lung
cancer. Dr. Dowlati is exploring the importance of the multiple
constitutively activated tyrosine kinase pathways in lung cancer.
He is selectively inhibiting pathways through the use of small
molecule inhibitors to determine the role of these pathways
in vitro, and translating successful molecules into clinical
trials. Dr Dowlati successfully developed a NIH K23 career development
award, “Translational assessment of Kinease Targets in
Lung Cancer” that was funded this year (7/1/04). Dr. Kern
is the mentor on this career development award.
Immunology/Inflammation/Acute Lung Injury
The theme of inflammation and acute lung injury is being developed
in the division. Currently one faculty member is actively working
in the area (Richard Silver, M.D., Associate Professor). 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
Acute Lung Injury is being explored as a member of the NIH ARDS
Network (Dr. Kern, PI). Cleveland Clinic is the ARDS Network
main member with UHC a collaborating site. UHC has all ARDS
Network protocols open and is accruing to these trials.
Clinical Research
Our clinical research is currently focused on pulmonary artery
hypertension (PAH). Under the direction of Robert Schilz, D.O.,
Ph.D, (recruited 2001) the PAH clinical research program has
developed over the past three years and forms the basis for
a growing clinical trials unit. Dr. Schilz has a national reputation
in PAH and is involved in the design and implementation of many
new PAH drug trials. Nurse coordinators, trained in techniques
of clinical research to complement their roles as patient coordinators
are in place . This group has developed/participated in multiple
clinical trials regarding new therapies for PAH. Currently,
five clinical trials are open and accruing patients through
our clinical research group:
a) Encysive FPH02X-STRIDE II extension-An Open –label
Study to Evaluate the Long term Safety of Sitaxsentan Sodium
Treatment with a Bosentan Arm in patients with Pulmonary Arterial
Hypertension.
b) Encysive FPH03- STRIDE III- A Long-term, Open-label Study
to Evaluate the safety of Sitaxsentan Sodium Treatment in Patients
with Pulmonary Arterial Hypertension
c) Myogen 320-ARIES 1-Ambrisentan in PAH –A phase III
Randomized, Double-blind, Placebo–controlled, Multicenter,
Efficacy Study of Ambrisentan in Subjects with Pulmonary arterial
Hypertension
d) Myogen 220-E – An Open –label, Long –term
Study of Ambrisentan in Pulmonary Hypertension Subjects Having
Completed Myogen Study AMB 220
e) United Therapeutics P01:13-A Multicenter, Randomized, Parallel,
Placebo-controlled Study of the Safety and Efficacy of Subcuntaneous
Remodulin Therapy after Transition from Flolan in Patients with
Pulmonary Arterial Hypertension: Phase IV Study.
This group is broadening its clinical research focus and has
recently submitted two grants in collaboration with outside
investigators in new areas
a) Idiopathic Pulmonary Fibrosis – In response to the
NIH RFA to develop a clinical research network, the clinical
research group developed a consortium of hospitals in the city
(UHC, VAMC, and Cleveland Clinic Foundation) and responded to
the RFA to become a NIH funded IPF clinical research center.
b) Diaphragm Paralysis – In collaboration with Ray Onders,
M.D., Department of Surgery, the clinical research group responded
to a recent RFA from the Amyotrophic Lateral Sclerosis Foundation
to develop diaphragm pacing in patients with ALS. The surgical
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.
