FACULTY

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Description of Research Interests

Richard Albert, M.D.

(Professor, DHMC)

COPD
Adult Respiratory Distress Syndrome
Health Services Research on Hospitalized Patients
Pulmonary Circulation
Mechanical Ventilation Acute Lung Injury
Respiratory Physiology

Basic research is focused on the effects of the prone position on ventilator-induced lung injury and gas exchange in the setting of acute lung injury. Clinical research is focused on COPD, the effects of obesity on the lung, and on health services research relating to the care of hospitalized patients.

David Badesch, M.D.

(Professor, UH)

Pulmonary Vascular Disease

Research involves an integrated, translational approach to the pathogenesis and treatment of pulmonary arterial hypertension (PAH). We are involved in multi-center clinical trials in patients with various forms of pulmonary hypertension, looking at prostacyclin analogs, phosphodiesterase inhibitors and endothelin receptor antagonists. In addition, we are pariticipating in a large, multicenter registry of patients with PAH. We also plan an investigator-initiated study of novel immunodulatory/ antiprolifertive therapy for PAH.

Ron Balkissoon, M.D.

(Associate Professor, NJMRC)

Asthma
COPD
Occupational Asthma
Vocal Cord Dysfunction
Environmental Tobacco Smoke

Research interests include translational and clinical studies in COPD and Asthma particularly use of exhaled biomarkers to characterize disease activity and response to therapy. Also clinical studies in vocal cord dysfunction and effects of environmental tobacco smoke on asthmatic children. Other collaboration involves comparison of airway changes (assessment of airway remodeling) in severe asthma versus COPD.

Michelle A. Beutz, M.D.

(Instructor, UH, CVP)

We are evaluating the role of the bioactive lipid, Sphingosine-1-Phosphate (S1P) in pulmonary hypertension. S1P is a relatively new lipid mediator which has recently been shown to regulate cell survival and proliferation, as well as vascular tone. We have demonstrated that S1P causes vasoconstriction in rat pulmonary artery rings and isolated perfused arteries. We are currently exploring how S1P is regulated by hypoxia.

Russell Bowler, M.D.

(Assistant Professor, NJMRC)

Acute Respiratory Distress Syndrome
Oxidant Lung Injury
COPD

Inflammatory Lung Disease (non-asthma)
We study the role of oxidative stress in several lung diseases, such as sepsis, lung fibrosis, and COPD. We are also using proteomics to study COPD and ARDS. We have knock-out and transgenic mice to study the primary extracellular antioxidant enzyme, extracellular superoxide dismutase (EC-SOD).

Kevin Brown, M.D.

(Assistant Professor, NJMRC)

Inflammatory Lung Disease (Non-Asthma)
Interstitial Lung Disease

Our laboratory performs clinical, translational and basic investigation into chronic inflammatory and fibrosing interstitial lung diseases. Specific areas of interest include:

• Relationship between inflammation and fibrosis in the injured lung
• Systemic autoimmune disease and its relationship to parenchymal lung disease
• Biologic markers of disease predilection, presence and activity
• Clinical characteristics of ILD
• Treatment trials in interstitial lung disease

Todd Bull, M.D.

(Assistant Professor, UCD)

Pulmonary Vascular Disease

My primary area of investigation is the role of the pulmonary vascular endothelial cells in the development of severe pulmonary hypertension. Currently this involves the investigation of human herpesvirus-8 infection of pulmonary endothelial cells and its effect on cell growth and apoptosis. I am also interested in developing non-invasive means of predicting the development of severe pulmonary hypertension by examining the gene expression of peripheral blood cells. Lastly, I am interested in the role of endothelial precursor cells (EPCs) in the formation of the plexiform lesions present in PAH.

Ellen Burnham, MD

(Assistant Professor, UH)

Acute Respiratory Distress Syndrome
Sepsis
Critical Illness

Research has focused on the effects of alcohol abuse on the lung, and how this relates to the development of critical illnesses such as pneumonia and ARDS, with an emphasis on how alcohol affects functioning of the alveolar macrophage. Additional interests include the effects of alcohol abuse on outcomes in critical illness. Other research has focused on the identification and characterization of stem cells in patients with acute lung injury, and how these can be manipulated for therapy of lung injury and sepsis.

Ethan Carter, Ph.D.

(Assistant Professor, CVP, DVAMC)

Pulmonary Vascular Disease
Respiratory Physiology

The primary area of investigation in my laboratory is the pulmonary vascular complications during liver cirrhosis. This condition is called hepatopulmonary syndrome. During hepatopulmonary syndrome, hypoxic pulmonary vasoconstriction is blunted or non-existent. The loss of hypoxic pulmonary vasoconstriction causes shunting of pulmonary arterial blood leading to systemic arterial hypoxemia. The cause of the blunted hypoxic pulmonary vasoconstriction is not known, but our recent work has demonstrated that activation of vascular smooth muscle potassium channels is central to the vasodilation and blunted hypoxic vasoconstriction. Our future work will search for the mediators responsible for the potassium channel activation as well as exploring the differences in the vasoreactivity between the systemic and pulmonary circulation during cirrhosis. A variety of methods from single cell studies to whole animal physiology are being employed in these studies.

A new area of investigation that my lab is actively pursuing is defining the endothelial determinants of vasculopathy during malaria. Malaria is the number one cause of mortality world-wide. The primary cause of death is organ failure due to vascular occlusion. Vascular occlusion is caused by cytoadherence of parasitized erythrocytes to vascular endothelium. We are actively investigating the role of nitric oxide and endothelial cell surface receptors such as CD36 and ICAM in this process.

In addition to my basic science research, I am the director of the exercise physiology laboratory at the Denver VA Medical Center. In this clinical laboratory we use exercise testing as a mechanism to assist in the diagnosis of pulmonary diseases.

Edward Chan, M.D.

(Associate Professor, NJMRC)

Inflammatory Lung Disease (Non-Asthma)
Interstitial Lung Disease
Tuberculosis

We are interested in the signaling pathways utilized by TNF��, LPS, and the mycobacterial cell wall component lipoarabinomannan in the induction of inducible nitric oxide synthase (iNOS) and nitric oxide (NO�~) in macrophages. We are also interested in the transcriptional regulation of iNOS by these stimuli and the mechanism(s) by which IL-4 suppresses this induction.

Ling-Yi Chang, Ph.D.

(Associate Professor, NJMRC)

Environmental and Occupational Lung Disease
Epithelial Cell Biology
Inflammatory Lung Disease (Non-Asthma)
Oxidant Lung Injury/Acute Lung Injury

Research interests center on the regulation of lung inflammation and leukocyte functions by oxidants, antioxidants, cytokines and cell adhesion molecules. An in vivo cell biology approach that utilizes ultrastructural morphology, morphometry, immuno-cytochemistry and in situ hybridization is emphasized.

Reuben Cherniack, M.D.

(Professor, NJMRC)

Asthma
COPD/Rehabilitation
Inflammatory Lung Disease (Non Asthma)
Interstitial Lung Disease
Respiratory Physiology

Pathophysiology of airway and interstitial disease. Correlation of structure and function.

Hong Wei Chu, M.D.

(Assistant Professor, NJMRC)

Asthma

Mycoplasma pneumoniae infection in mouse models of allergic asthma

Airway epithelial mucus production and regulation by an allergic milieu

COPD

Effects of cigarette smoke exposure on airway epithelial cell VEGF expression

The impacts of cigarette smoke exposure on host innate immune response to infections. My focus is on small airway epithelial cells.

Christopher Coldren, Ph.D.

(Assistant Professor)

Neoplastic Lung Disease
Pulmonary Vascular Disease
Adult respiratory Distress Syndrome
Oxidant Lung Injury/Acute Lung Injury
Sepsis
Cystic Fibrosis

My interest is in the application of microarray technologies to the study of lung diseases. I have several ongoing projects, and collaborate with many groups within the Pulmonary Division and the UCCC. For the past several years we have employed gene expression microarrays for these studies; recently we have begun to use a related technology for gene copy number analysis for high resolution genomic analysis of neoplastic lung diseases.

Carlyne Cool, M.D.

(Associate Professor)

Interstitial Lung Disease
Pulmonary Hypertension

Translational research and basic investigation into the pathogenesis of severe idiopathic pulmonary arterial hypertension and mechanisms of pulmonary fibrosis.

Adela Cota-Gomez, Ph.D.

(Instructor, UCD)

Inflammatory Lung Disease (non-asthma)
Lung Immunology

Our research focuses on the cellular effects of viral products and how these relate to human disease. We hope that by determining the contributions of viral proteins to disease we can develop better therapeutic interventions against viral infections. Specifically, we are studying the cellular responses to the HIV-1 Tat protein. In addition to its function as a regulator of viral gene expression, this protein has a number of cellular effects. Among these, we have observed induction of oxidative stress, inappropriate activation of immune responses, and gross morphological alterations. Our research suggests that these effects of extracellular Tat can further aggravate the immunodeficiency of AIDS patients, and/or induce vascular and tissue damage even in viral-free organs. Thus, the Tat protein should be considered an important player in HIV pathogenesis that directly and indirectly contributes to the great morbidity and mortality of HIV AIDS and as such should be a target of therapeutic HIV interventions.

James D. Crapo, M.D.

(Professor, NJMRC)

Oxidants and Antioxidants in Chronic Lung Diseases
Chronic Obstructive Pulmonary Disease

The major research focus is on the role of oxidants and antioxidants in modulating lung responses to acute and chronic forms of injury. A major focus is on the role of extracellular superoxide dismutase in the pathogenesis of asthma and COPD. New catalytic antioxidants are being developed and tested for efficacy in animal models of these diseases. Cell and molecular biology techniques are combined with immunopathology and morphometry to elucidate the pathogenesis of how the lung responds to a variety of potentially toxic insults. The primary genes involved in the pathogenesis and expression of COPD are being explored through genetic epidemiology.

Joseph T Crossno, Jr. M.D., Ph.D.

(Assistant Professor, DVAMC, UH, Cardiovascular Pulmonary Laboratory (CVP))

Pulmonary Vascular Disease

My research focuses on Peroxisome Proliferator-Activated Receptors (PPARs) which are members of a nuclear hormone receptor superfamily of ligand-activated transcription factors which bind structurally diverse ligands including long-chain fatty acids, eicosanoids, thiazolidinediones, and fibrates. Once bound activated PPARs form obligate heterodimers with the 9-cis retinoic acid receptor, RXR. These PPAR - RXR heterodimeric complexes become transcriptionally active at PPAR response elements (PPRE) and alter the expression of target genes. The PPAR isoform, PPARg, is expressed in vascular endothelial cells and vascular smooth muscle cells (VSMC) of the systemic and pulmonary vascular system. PPAR signaling pathways have been reported to exert anti-inflammatory effects and attenuate the development of atherosclerosis. However, the mechanisms responsible for their antiatherosclerotic effects remain largely unknown. We have found that PPAR? agonists attenuate and reverse hypoxia-induced pulmonary vascular remodeling and are currently working toward understanding the molecular pathways involved in PPARg-mediated vasculoprotective events.

Lung Development and Transplantation

The PPAR family of transcription factors is critically important in lung development from a vasculogenesis and alveologenesis prospective. I am also interested the role of endothelial dysfunction in acute lung injury following lung transplantation and the potential beneficial role that PPARg agonists may have in preventing and reducing ischemia-reperfusion injury.

Charles Daley, M.D.

(Professor, NJMRC)

Tuberculosis
Nontuberculous Mycobacterial Infections
Respiratory Infections
Bronchiectasis

Research interests include clinical trials of new antibiotics and treatment regimens for mycobacterial infections, epidemiologic studies including molecular epidemiology of mycobacterial infections and evaluation of new diagnostic tests.

Brian Day, Ph.D.

(Associate Professor, NJMRC)

Oxidant Lung Injury/Acute Lung Injury
Cystic Fibrosis
COPD
Chronic Beryllium Disease
Neoplastic Lung Disease

My research focuses include: 1) development of catalytic antioxidant metalloporphyrins as possible therapeutic modalities in disease states involving the overproduction of reactive oxygen species; 2) the role of extracellular lung antioxidant defenses in the etiology of lung pathophysiology of cystic fibrosis and chronic obstructive pulmonary disease; 3) role of oxidants in chronic beryllium disease; and 4) the development of agents that induce thiol efflux in tumor cells as sensitizers for radio- or chemotherapy.

Edward Dempsey, M.D.

(Professor, DVAMC, UH, CVP)

Pulmonary Vascular Disease
Chronic Obstructive Pulmonary Disease
Neoplastic Lung Disease

Research interests include:

• Role of selected neuropeptides, peptidases, and intracellular kinase cascades in the pathogenesis of chronic hypoxic pulmonary hypertension.
• Crosstalk between resident pulmonary vascular cells and circulating progenitor cells in injury and repair.
• Factors that regulate mobilization and engraftment of circulating progenitor cells into the lung circulation.
• Identification of genes that modify susceptibility to chronic hypoxic pulmonary hypertension.
• Discovery and testing of novel treatments for pulmonary hypertension.
• Studies in knockout and transgenic mice, rats, cows and humans and relevant cells; cellular and molecular methods; gene and protein arrays.

Other interests include unexplained hypoxemia, reactive polycythemia and early detection of lung cancer.

Ivor S. Douglas, M.D.

(Assistant Professor, DHMC, DL)

Acute Respiratory Distress Syndrome
Interstitial Lung Disease
Oxidant Lung Injury/Acute Lung Injury
Pulmonary Vascular Disease
Sepsis
Critical Care Outcomes

Dr. Douglas studies mechanisms of lung repair in response to acute and subacute lung injury using whole animal, translational and cellular/molecular strategies. Current studies focus on Wnt-Catenin signal transduction repair and remodeling in a murine oxidant stress ALI model. Dr. Douglas is Co-PI for the Acute Respiratory Distress Syndrome Network, and PI for several multicenter investigations in sepsis, ARDS, hypercalcemia of critical illness, sedation, critical care outcomes and knowledge engineering in critical care.

Karen Fagan, M.D.

(Associate Professor, CVP, UH)

Pulmonary Vascular Disease
Pulmonary Hypertension
Critical Care
Pulmonary Pathophysiology

The focus of our research is on the pathogenesis of pulmonary hypertension. We are interested in the effects of intermittent hypoxia, similar to that see in sleep apnea, on the control of pulmonary vascular tone. We are especially interested in the role of oxidative stress and the effects on nitric oxide and gene expression. In a separate project, we are investigating the role of inflammatory cytokines, especially IL-6, in the pathogenesis of pulmonary hypertension using animal models of PH. The lab employs a variety of techniques from animal surgery and physiology to molecular biology protocols. I also serve as the director of the pulmonary pathophysiology course for the medical students emphasizing the application of physiology to pulmonary diseases they will encounter during their training and in practice. Fellows and other faculty participate heavily in the teaching of this course.

James Fisher, M.D.

(Professor, DHMC)

Epithelial Cell Biology
Innate Pulmonary Defense Mechanisms
Lung Inflammation

Surfactant proteins have crucial roles in the regulation of surfactant homeostasis. Recently this laboratory has developed mice that are null or alternatively overexpress SP-D, demonstrating that SP-D is the most important surfactant protein to date in regulating the abundance of alveolar surfactant. However, it is also apparent that SP-D is an important regulator of innate pulmonary immunity. We have shown that SP-D has an important role in resistance to tuberculosis and MAI infections. We have mouse models that express varying amounts of normal or genetically modified SP-D to evaluate that role. SP-D also alters the pulmonary inflammatory response to endotoxin by unknown mechanisms. in the absence of SP-D there are marked increases in pulmonary alveolar macrophages and activation of T lymphocytes. We have identified the binding domain of SP-D responsible for such activity. The basis for this activation may be abnormal antigen recognition and/or processing. This SP-D may have a role in common inflammatory diseases such as IPF and asthma. Future work will be directed towards understanding the mechanisms by which SP-D regulates pulmonary inflammation.

Sonia Flores, Ph.D.

(Associate Professor, Pulmonary Division)

Inflammatory Lung Disease (Non-Asthma)
Oxidant Lung Injury/Acute Lung Injury
Pulmonary Vascular Disease

Effects of the secreted HIV-1 Tat protein on cellular redox status and endothelial cell biology, including adhesion molecule expression and NF-kB activation.

Pro-inflammatory properties of HIV-1 Tat in animal models of pulmonary injury.

Regulation of Mn-superoxide dismutase expression under pathological conditions.

Role of HIV-1 Nef protein on pathogenesis of pulmonary hypertension

Intersection between autoimmunity and oxidant stress in endothelial dysfunction in Type 1 diabetes.

Andrew Fontenot, M.D.

(Associate Professor, UH)

Inflammatory Lung Disease (Non-Asthma)
Interstitial Lung Disease
Granulomatous Lung Disease
Immunology

Recent research has focused on T cell recognition in noninfectious granulomatous lung disease (in particular, sarcoidosis and chronic beryllium disease). We are also investigating the binding of beryllium to class II major histocompatibility complex molecules with the goal being the identification of the beryllium/peptide/MHC complex. Other ongoing projects include investigating the immune basis of emphysema and hypersensitivity pneumonitis.

Stephen K. Frankel, M.D.

(Assistant Professor, NJMRC)

Interstitial Lung Disease
Inflammatory Lung Disease (Non Asthma)

Current research focuses on (1) the normal regulation of fibroblast and myofibroblast populations within the lung and how these mechanisms become dysregulated in interstitial lung disease and pulmonary fibrosis and (2) treatment trials in interstitial lung disease.

Bifeng Gao, Ph.D.

(Assistant Professor, UCD)

Adult Respiratory Distress Syndrome
Oxidant Lung Injury/Acute Lung Injury

My research interests include:

Genetic and chemical modification of superoxide dismutases and optimizing the pharmacological properties of the modified superoxide dismutases for adult respiratory distress syndrome and hypertension.

Using transgenic mice models and gene microarray technology to study the role of prostacyclin synthase in vascular biology and lung injury.

Sarah Gebb, PhD

Hypoxia in Development and Disease

The role of oxygen tension in normal lung development and disease is the central focus of my research. Normal fetal growth and development occur in an environment that is hypoxic relative to most normal adult tissues. This is especially true of the lung which develops in utero at oxygen concentrations equivalent to 3-5% oxygen and transitions rapidly at birth to one of the highest oxygen environments of the internal organs with alveolar oxygen tensions approximating 16% oxygen. It is apparent that the low oxygen environment of the fetus is necessary for normal lung growth and development in utero, and by the same token that appropriate transition to higher oxygen tension at birth is important for postnatal lung maturation. By extension, the normal lung developmental program is disrupted in the setting of inappropriate oxygen tensions as with premature birth (hyperoxia) or failure of the term neonate to transition to air breathing at birth (sustained hypoxia). Thus the long term goals of my research are three fold: 1) to understand how the low oxygen environment of the fetus drives normal lung development in utero, 2) to understand how maintenance of the low oxygen (hypoxic) environment postnatally inhibits normal lung maturation, and 3) to understand how a return to the low oxygen (hypoxic) environment in the adult may precipitate or perpetuate lung pathology (COPD, Cancer or Asthma).

Mark Geraci, M.D.

(Professor, UH, DL, DVAMC)

Epithelial Cell Biology
Neoplastic Lung Disease

My research centers on two major projects: 1) The role of prostacyclin in both pulmonary vascular disease and lung cancer and 2) Application of expression analysis to study disease pathogenesis. Prostacyclin in Pulmonary Vascular Disease: Pulmonary hypertension (PH) refers to a spectrum of diseases, where the pulmonary artery pressure is elevated. Recently, a new classification of pulmonary hypertension has been proposed. We hypothesized that selective pulmonary overexpression of PGIS may prevent the development of pulmonary hypertension. Histologic examination of the lungs revealed nearly normal arteriolar vessels in the Tg+ mice in comparison with vessel wall hypertrophy in the Tg- mice. Thus, Tg+ mice were protected from the development of pulmonary hypertension after exposure to chronic hypobaric hypoxia. We conclude that PGIS plays a major role in modifying the pulmonary vascular response to chronic hypoxia and are continuing to investigate the molecular mechanisms for this action.

Prostacyclin and Lung Cancer Chemoprevention:

Inhibition of cyclooxygenase (COX) activity decreases eicosanoid production and prevents lung cancer in animal models. Prostaglandin I2 (PGI2, prostacyclin) is a prostaglandin H2 (PGH2) metabolite with anti-inflammatory, anti-proliferative, and anti-metastatic properties. The instability of PGI2 has limited its evaluation in animal models of cancer. We hypothesized that pulmonary overexpression of prostacyclin synthase (PGIS) may prevent the development of murine lung tumors. The transgenic mice exhibited significantly reduced lung tumor multiplicity (tumor number) in proportion to transgene expression, a dose-response effect. These studies demonstrate that manipulation of prostaglandin (PG) metabolism downstream from COX produces even more profound lung cancer reduction than COX inhibition alone. These studies have led to the recently funded trial of Iloprost (an oral prostacyclin analogue) in Lung Cancer Chemoprevention.

Expression Analysis to Study Disease Pathogenesis: In 1999, Dr. Mark Geraci was selected as the Director of the Gene Expression Facility by the UCD leadership and charged with the development of all aspects of the Facility. Gene microarray technology now permits the analysis of the gene expression profile of lung tissue obtained from patients with primary pulmonary hypertension with that found in normal lung tissue. Cluster analysis can give clues to the pathogenesis by displaying genes whose expression is altered in a coordinate manner. Although the number of patient samples was small, gene dendogram, cluster analysis and concordant expression differences show that there are categorical and robust differences in the profile of expressed genes between structurally normal lungs, lungs from patients with sporadic PPH and lungs from patients with FPPH. Currently, we are investigating expression profiling in murine models of lung cancer, human lung cancer, cystic fibrosis, idiopathic pulmonary fibrosis, and acute respiratory distress syndrome.

Todd Grazia, M.D.

(Assistant Professor, UH)

Lung Transplantation

I have a specific interest in defining the potential role of the microvascular component in the immune response of primarily vascularized thoracic allografts. Specifically, I have been working out the role of the endothelial cell (EC) as a potential antigen presenting cell (APC) and/or a target of the cellular immune response in thoracic transplantation utilizing a mouse model of primarily vascularized cardiothoracic organ transplantation (heterotopic murine heart transplant model) and evaluation of human heart and lung allograft biopsy tissue. Thus far, we have demonstrated that the required effector T-cell (CD4+) requires MHC II expression on donor hematopoietic cells that act as APCs and that the allograft EC is the required MHC II-restricted target of the response. Based on these results, we have identified a potential mechanism to explain the theoretical protective effect of recipient to donor endothelial chimerism against acute rejection in solid organ transplant patients. Specifically, if donor endothelial cells are targets of effector T-cells, increasing the number of non-antigenic (host-derived) endothelial cells will decrease the number of targets available. We have also elucidated the in vivo requirements for effector CD4+ T-cell killing. Specifically, we have demonstrated that the effector CD4+ T-cell requires concomitant T-cell perforin and target cell Fas expression for in vivo killing. This is a paradigm shift and the first time to our knowledge that a CD4+ T-cell has been demonstrated to require a cytolytic phenotype to kill in vivo. Additionally, we have now demonstrated that in fact the CD8+ T-cell can also function as an important effector of cardiac rejection once activated by some other immune helper cell (presumably the CD4+ T-cell). Comparative genomic analysis of cardiac allografts rejecting either by activated (primed) CD8+ T-cells or na�ve CD4+ T-cells demonstrated significant upregulation of perforin and granzymes in both scenarios. Based on these genomic observations, we have begun plans to look at peripheral blood soluble perforin levels (via PCR) to determine if this may be a distinguishing biomarker of rejection in human heart and lung transplant patients. Consequently, our future plans are to further define the in vivo requirements for CD4+ T-cell killing and primed CD8+ T-cell killing and to further pursue genomic analysis in human tissue and peripheral blood to define potential biomarker(s) of rejection. Finally, we will continue to assess endothelial chimerism in human tissue, in a prospective controlled fashion, to determine if minimizing donor endothelial targets is protective against rejection.

Michael Gruber, M.D.

(Instructor, UH)

Chronic Obstructive Pulmonary Disease
Acute Lung Injury

My research consists of microarray gene expression analysis in lung tissue and human peripheral blood mononuclear cell (PBMC) samples in several disease states to identify candidate genes of interest and potential biomarkers of illness. Currently, I am involved in a project investigating gene expression in various anatomic regions of normal human lung from demographically diverse individuals which will provide insight into inter- and intraindividual gene expression patterns in the lung as well as an extensive comparative database for the study of lung samples in different disease states. Second, I am investigating gene expression patterns as biomarkers of clinical outcomes in both COPD and acute lung injury.

Michael Hanley, M.D.

(Professor, DHMC)

Adult Respiratory Distress Syndrome
Critical Care Disaster Preparedness
Pneumonia

Clinical interests include ventilator management of patients with ARDS, risk stratification / management of pneumonia, and disaster preparedness in medical critical care units. Current research projects include developing a model of cross-training to meet the respiratory needs of patients in mass casualty events.

Leonid Heifets, M.D., Ph.D.

(Professor, NJMRC)

Mycobacterial Disease

Search for new antimicrobial agents against Mycobacterium tuberculosis and Mycobacterium avium. Development of a new drug delivery system through incapsulation into nanoparticles. Evaluation of in vitro activity of various new antimycobacterial drugs singly and in combinations. Development and evaluation of new methods for rapid isolation, speciation and drug susceptibility testing of mycobacteria. Introduction of newly developed (and patented) agar medium for M.tuberculosis. Etiology (mucobacterial?) of the bowel chronic disease.

Janet Henson, B.S.

(Instructor, NJMRC)

Asthma
Infectious Disease
Inflammatory Lung Disease (Non asthma)
Interstitial Lung Disease
Acute Lung Injury

Cell Biology of Inflammation. Initiation, progression, resolution and mediator control of the inflammatory process. Histopathological and ultrastructural evaluation of tissues.

Peter Henson, Ph.D.

(Professor, NJMRC)

Adult Respiratory Distress Syndrome
COPD
Inflammatory Lung Disease
Interstitial Lung Disease
Infectious Disease
Oxidant Lung Injury/Acute Lung Injury

Cell biology of inflammation and its consequences. Our group focuses on the initiation, progression, resolution and mediator control of the inflammatory process, extending from the biochemical, molecular and cellular levels to animal systems and patient investigation. Cells include neutrophils, eosinophils, mononuclear phagocytes, lymphocytes, platelets and endothelial cells with a particular interest in the process of apoptosis as it applies to resolution of inflammatory reactions. Normal homeostasis in the lung is suggested to involve significant cell turnover (apoptosis and replacement) and, disruption of these processes are implicated in a number of inflammatory and non-inflammatory pulmonary diseases.

Daniel Hernandez-Saavedra, Ph.D.

(Instructor, WWRI)

Lung Cancer and Oxidant Injury

Our study focuses in the relationship between the regulation of Mn-superoxide dismutase expression and cancer. We have identified polymorphisms in two regulatory regions of the sod2 gene. Currently, we are working in the identification of polymorphisms that disrupt the sod2 gene regulation of expression and that can be used as risk markers for development of lung and prostate cancer.

Michael Iseman, M.D.

(Professor, NJMRC)

Mycobacterial Disease

Clinical mycobacterial disease, pathogenesis, diagnosis, treatment, and prevention. Particular emphasis on multidrug-resistant tuberculosis, M. avium, M. chelonae, and M. abscessus. Novel issues include the anatomical, biochemical, and genetic basis for the nodular-bronchiectatic form of MAC disease seen in slender females with mitral valve prolapse, scoliosis, pectus excavatum, and disease of the right middle lobe and lingula. Predisposing factors thus far identified include CF, alpha-1-antitrypsin and cryptic aspiration.

William Janssen, M.D.

(Assistant Professor, UH, NJMRC)

COPD
Acute Respiratory Distress Syndrome
Inflammatory Lung Disease (non-asthma)

Clearance of apoptotic cells is essential for resolution of lung injury and lung homeostasis. Our laboratory performs basic, translational, and clinical research investigating the role of apoptotic cell clearance in acute and chronic inflammatory lung diseases. Specific areas of interest include: monocyte trafficking during inflammation, mechanisms of apoptotic cell clearance during acute lung injury and emphysema, and factors that drive stem cell mobilization and recruitment during pulmonary inflammation.

Robert Keith, M.D.

(Associate Professor, DVAMC, UH)

Neoplastic Lung Disease
Advanced Bronchoscopy
COPD
Epithelial Cell Biology

Lung cancer remains the number one cancer killer in men and women in the United States. Our research interests focus on the early detection and chemoprevention of lung cancer. Specifically, we are examining prostaglandin manipulation and PPAR gamma agonists in pre-clinical models of non-small cell lung cancer, including genetically modified mice. An NCI sponsored human trial of Iloprost (an oral prostacycin analogue) is currently in progress and future trials are in the planning stage. Our chemoprevention trials include performing fluorescence bronchoscopy, and we also perform endobronchial ultrasound guided TBNA, electromagnetic navigational bronchoscopy, and electrocautery. Fluorescence bronchoscopy allows for improved detection of pre-malignant central airway lesions and we are better characterizing these lesions in terms of lung cancer biomarker discovery and validation. We are also beginning to investigate the connection between altered prostacyclin synthase expression and the development of COPD.

Dwight J. Klemm, Ph.D.

(Professor, CVP)

Pulmonary Vascular Disease

Research in my laboratory focuses on three areas. The first area comprises studies to identify and define molecular events that control smooth muscle cell (SMC) proliferation and migration that contribute to the vascular remodeling observed in certain forms of pulmonary hypertension, atherosclerosis, and restenosis. These studies have demonstrated that the transcription factor, cAMP Response Element Binding Protein or CREB, plays a central role in controlling SMC growth, migration, and survival. Ongoing experiments are investigating the signaling systems that regulate CREB levels and function in SMCs, and exploring the mechanisms by which CREB controls SMC phenotype. This research has highlighted a number of novel biochemical and molecular mechanisms that may have a profound impact on pathological vascular remodeling, and that may serve as targets for new therapies designed to prevent or treat pulmonary and systemic vascular disease. In addition, we have recently initiated translational studies to evaluate the impact of thiazolidinediones, a class of antidiabetic drugs, on pulmonary vascular remodeling in a rat model of primary pulmonary hypertension.

The second area of research focuses on the molecular mechanisms that regulate fat cell development and survival. These studies were the first to demonstrate that CREB initiates the formation of new adipocytes and prevents their death by apoptosis.. In addition, we have initiated translational studies to evaluate CREB and other adipocyte-specific factors in the regain and redistribution of fat associated with suction lipectomy, and to examine CREB�s role in the loss and redistribution of fat in HIV-related lipodystrophy.

The third and most recent area focuses on the ability of bone marrow-derived progenitor cells to traffic to adipose tissue and become adipocytes with a unique phenotype. Our data suggest that mesenchymal progenitors from bone marrow become mulitlocular adipocytes with high mitochondrial content, but lack uncoupling protein-1. Thus, the novel adipocyte population has characteristics different from either conventional white or brown adipocytes. The results also suggest that the origin of fat cells and the development of adipose tissue is far more complex than previously assumed. Experiments are currently underway to firmly identify the progenitor cell population, investigate mechanisms that promote trafficking of progenitor cells to adipose tissue, and evaluate the function of the novel adipocyte population.

James Lavelle, M.D.

(Instructor/Fellow, UH, NJMRC)

Acute Respiratory Distress Syndrome
Mechanotransduction
Interstitial Lung Disease

I study the response of lung cells to mechanical strain. I am currently working with epithelial cells and fibroblasts from cell lines and from patients with and without interstitial lung disease. I focus on mechanoregulation of the myofibroblast phenotype and the relationship of this to proliferation and survival, which is of particular importance in idiopathic pulmonary fibrosis. I am also interested in signal transduction and mechanisms of epithelial cell membrane injury and repair.

Teofilo Lee-Chiong, M.D.

(Associate Professor, NJMRC)

Research interests center on a number of sleep disorders, including obstructive sleep apnea and restless legs/periodic limb movement disorder, parasomnias and insomnia.

David Lynch, M.B.

(Professor, NJMRC)

Asthma
Environmental and Occupational Lung Disease
Interstitial Lung Disease

Quantification and characterization of interstitial lung disease on CT by visual and computer-based methods.

Assessment and quantification of obstructive lung disease by CT.

Dennis Lyu, M.D.

(Instructor/Fellow, UH)

We hypothesize that in lung transplantation patients that develop community-acquired respiratory infections, the production of chemokines and cytokines in the lung creates an inflammatory reaction that can eventually lead to the development of chronic rejection, which is clinically manifested as bronchiolitis obliterans syndrome (BOS). Using the cohort of lung transplantation patients in the University of Colorado Lung Transplant Program that develop viral infections, I am currently using samples from patients to study the following aims. (1) Determine whether a set of genes and proteins are differentially expressed in bronchoalveolar lavage (BAL) cells following viral infections in lung transplantation patients. This aim will test the hypothesis that a defined pattern of genes and proteins following virus infection in lung transplantation patients is correlated with the subsequent development of bronchiolitis obliterans syndrome. (2) Determine whether Foxp3+CD25+CD4+ cells are inappropriately elevated following viral infections in the setting of lung transplantation. This aim will test the hypothesis that Foxp3+CD25+CD4+ cells, which are normally increased to regulate inflammation, will be inadequately elevated in viral infections in lung transplantation patients that progress to chronic rejection.

Lisa Maier, M.D., MSPH

(Associate Professor, NJMRC)

Interstitial Lung Disease
Environmental and Occupational Lung Disease

My research focuses on defining genetic and exposure risk factors along with disease mechanisms in occupational, environmental and idiopathic granulomatous and interstitial lung diseases. My laboratory utilizes genetic and molecular epidemiologic tools to assess genetic risk factors and their function that are associated with the development of two granulomatous lung diseases, chronic beryllium disease (CBD) and sarcoidosis. CBD occurs in a subset of workers exposed to beryllium, after they have developed a precursor to disease, beryllium sensitization; exposure to beryllium is necessary for the development of sensitization and disease and we are defining the variable important in this exposure response relationship, along with gene by environment interactions in CBD and sensitization. In conjunction with other investigators, we are assessing potential exposures important in the development of the sarcoidosis, a granulomatous lung disease of unknown etiology. We are also investigating genetic factors shared by these two disease and those involved in more severe forms of these granulomatous lung diseases, along with the functional aspects of these susceptibility factors from a mechanistic standpoint. This translational work has implications for therapeutic and preventive interventions that we hope to move from the lab to the workplace/bedside.

Barry Make, M.D.

(Professor, NJMRC)

COPD / Pulmonary Rehabilitation Respiratory Physiology

My research focuses on the pathophysiology of COPD and outcomes of therapies for COPD. Goals of current projects include:

• Assess outcomes of new therapeutic agents and novel treatment approaches.
• Assess methods to reduce and treat acute exacerbations of COPD.
• Determine the minimal clinically important difference of outcome measures in COPD.
• Improve the diagnosis of COPD in community and medical settings.
• Evaluate the efficacy of long-term oxygen therapy for expanded indications in COPD.
• Evaluate the role of pulmonary rehabilitation in reducing mortality in COPD

James Maloney, M.D.

(Associate Professor, VAMC and UCD)

Acute Lung Injury (ALI)
Pulmonary Vascular Diseases

Genetic Risk factors for incidence and severity of Acute Lung Injury and Sepsis: This translational research is funded by an NIH RO1 mechanism investigating the potentially injurious functional effects of common genetic variants in thrombospondin-1 (TSP1) in vitro and evaluating their association with these diseases by using DNA specimens and illness data from Ali and sepsis subjects recruited for the project. A subcontract on an NIH ALI SCCOR grant centered at Johns Hopkins supports contribution of anonymous DNA specimens and linked data used in the TSP1 research for more global use in evaluating common variation in many other candidate genes as risks for ALI susceptibility and severity.

Genetic risk factors for pulmonary arterial hypertension (PAH) and pharmacogenomics on the endothelin pathway in PAH: Preliminary data reveals common missense genetic variants in the endothelin-A receptor (EDNRA). We have also successfully transfected wild type EDNRA into human cells in order to begin study of missense receptor effects on ET1 signaling pathways.

Genetics of the hypoxia-ischemia response pathway: Preliminary data has been generated looking at VEGF common variants and the risk of acute mountain sickness. So far a VEGF polymorphism that appears to de-stabilize VEGF mRNA has been found to be protective against acute symptoms related to hypoxic exposure (acute mountain sickness, or AMS). Mechanisms of alternative splicing of TSP1 and TSP1 transcription in response to hypoxia is funded under �1� above. A more extensive genetic association study of AMS with multiple candidate gene variants in the hypoxia response pathway in 1000 subjects who travel to Colorado mountain altitudes will be completed over the 2006-8 Winter seasons.

Richard Martin, M.D.

(Professor, NJMRC)

Asthma
COPD

We evaluate the inflammation (cellular profiles and mediators), bronchial reactivity, and pulmonary physiology of asthma and COPD both in human and mouse models (bench to bedside). Additionally, a recent major emphasis is to investigate the potential of chronic mycoplasma and chlamydia infection in the pathogenesis of asthma and COPD both in human and animal models. The mouse models include the interaction between allergen and infection (Hygiene hypothesis) leading to �asthma:� and cigarette smoke and infection leading to emphysema. These studies are funded by NIH/NHLBI and industry.

Robert Mason, M.D.

(Professor, NJMRC)

Surfactant and Alveolar Type II Cells
Alveolar epithelial cells and viral infections

Our laboratory has two main projects. The first is on the regulation of lipogenesis as related to surfactant production by alveolar type II epithelial cells. We have shown that keratinocyte growth factor (FGF-7) regulate fatty acid synthesis via akt activation and SREBP-1c. Recently, we have cloned a novel lypophosphatidylcholine aceyltransferase that is likely to be important in surfactant synthesis. Our current studies are focused on regulation of lipogenesis in type II cells and regulating this novel aceyltransferase.

The second project focuses on the role of the alveolar epithelial response to viral infections. The epithelium plays an important role in innate immunity. We are currently studying coronaviruses including SARS coronavirus. For these studies, we have developed techniques for isolating adult human type II cells and maintaining them in a highly differentiated state. We are currently studying the biologic effects of viral infection in alveolar epithelial cells with an emphasis on their role in the innate immune response.

Joe McCord, Ph.D.

(Professor, WWRI)

Oxidant Lung Injury/Acute Lung Injury

I am interested in the mechanisms of oxygen-derived free radical generation in various models of inflammatory or ischemic injury to heart or lung. The concept of oxidant/antioxidant balance is being tested, and the physiological and biochemical consequences of imbalance are being determined, especially with regard to lipid peroxidation and events leading to fibrosis. Restoration of normal oxidative balance by the up regulation of endogenous antioxidant enzymes is being explored as a therapeutic approach.

York Miller, M.D.

(Professor, DVAMC)

Epithelial Cell Biology
Neoplastic Lung Disease
COPD/Rehabilitation

My research interest is in the process of carcinogenesis in the lung. Multiple genetic and epigenetic aberrations are found in the respiratory epithelium of smokers; the challenge is to understand which of these predict the development of lung cancer and which can be manipulated to prevent lung cancer. Active projects include:

• Analysis of the association of respiratory epithelial biomarkers and lung cancer.
• Lung cancer chemoprevention studies in humans.
• Use of transgenic and null mutant mice for study of susceptibility to and chemoprevention of lung cancer.
• Role of neuropeptides in pulmonary diseases, particularly lung cancer, pulmonary hypertension and COPD.

Marc Moss, M.D.

(Professor, UH)

Acute Respiratory Distress Syndrome
Acute Lung Injury
Alcohol Abuse and Dependence and Critical Illness
Sepsis

My research examines the mechanisms by which alcohol abuse and dependence increase susceptibility to acute lung injury. In addition, we are exploring the effects of a variety of therapeutic modalities for patients with ARDS in NIH sponsored clinical trials. Finally, we are interested in the development of acute neuromuscular dysfunction in patients with severe sepsis and acute lung injury.

Sally K. Nelson, Ph.D.

(Associate Clinical Professor of Medicine)

Oxidative Stress and Disease

Dr. Nelson is interested in free radical biochemistry and as it relates to diseases that have an oxidative stress component. Her areas of research interests include aging, Heart/organ preservation and Transplantation chemistry, Amyotrophic Lateral Sclerosis (Lou Gehrigs disease), Pre-eclampsia, Diabetes and Heart Disease. Interested in identifying genetic mutations and polymorphisms in iron regulatory proteins as risk factors for preclampsia. Developed a unique organ preservation solution that extends the period of heart preservation from the current window of 4 to 24 h. She plans to show that preservation of donor hearts in this solution suppresses free radical induced damage to the graft and prevents organ failure and immuno rejection in heart transplantation models. Also interested in phytochemicals that modulate the expression of endogenous antioxidant systems which have a positive effect on oxidative stress markers in humans.

Lee Newman, M.D.

(Professor, UH, Dept. Preventive Medicine and Biometrics; Dept. Medicine)

Environmental and Occupational Lung Disease
Sarcoidosis
Inflammatory Lung Disease

Basic:

We investigate the immunologic and inflammatory mechanisms of lung disease, particularly related to how metal antigens induce granuloma formation, cytokine gene regulation., and HLA x T cell interaction.

Translational:

We study the genetic and immune basis of lung disorders and their interaction with environmental exposures. We are interested in how these mechanisms affect susceptible populations at risk. The principal focus is on the interactive role of T cells, macrophages and the mediators they produce in granulomatous diseases. Diseases of interest include sarcoidosis, chronic beryllium disease, and the pneumoconioses. The emphasis is on patients with granulomatous disease, examining individual susceptibility, developing new biomarkers of disease and of prognosis using proteomic and biochemical approaches.

Epidemiologic:

We conduct epidemiologic research examining the environmental determinants of lung disease (emphysema, sarcoidosis, occupational disorders) using a multidisciplinary approach.

Jerry A. Nick, M.D.

(Associate Professor, NJMRC)

Cystic Fibrosis
Inflammatory Lung Disease (Non-Asthma)
Adult Respiratory Distress Syndrome

Basic:

My primary research interest is the intracellular signaling mechanisms that allow human neutrophils to coordinate response to pro-inflammatory stimuli, and regulate the intensity response. In particular, we have focused on the MAP kinase signaling cascades, as these are central regulators of a broad range of stress responses by the neutrophil. We are interested in the use of a coordinated functional genomics analysis to study the response of the neutrophil to P. aeruginosa in the context of CF, and to LPS in the context of ARDS. As a secondary research interest, we have discovered that neutrophils enhance the development of Pseudomonas aeruginosa biofilms, and we are interested in identifying mechanisms by which the presence of neutrophils modifies the virulence of P. aeruginosa, and novel therapeutic approaches based on the interactions between neutrophils and P. aeruginosa.

Clinical:

Through the Cystic Fibrosis Foundation Therapeutic Development Network, our Adult CF program actively participates in a number of ongoing research trials involving new diagnostic and therapeutic approaches to the treatment of CF. We are typically involved in 3-5 Multicenter trials and 1-2 Local Investigator initiated trials at any one time. A number of additional �Translational� protocols are ongoing, which allow for collection and analysis of blood and tissue from CF patients in a variety of clinical settings.

Mark Nicolls, M.D.

(Associate Professor, UH)

Lung and Islet Transplantation, Immune Aspects of Pulmonary Hypertension

Our laboratory�s focus is on transplantation science and autoimmunity in pulmonary disease. Research efforts target immune and non-immune mechanisms of allograft acceptance. Specifically, we have established an experimental lung transplant model and are examining immune tolerance and airway fibrosis in this system. We are also actively investigating the contribution of the immune system to the development of pulmonary hypertension. In addition to these pulmonary-related studies, we are utilizing emerging proteomic technologies to evaluate pancreatic islet transplant stress. A principal focus is establishing viability biomarkers to facilitate more successful human islet transplantation as a cure for Type I diabetes.

Thomas Petty, M.D.

(Professor)Chairman,National Lung Health Education Program

Adult Respiratory Distress Syndrome (Clinical)
COPD/Early Diagnosis and Rehabilitation

Conducting research in the early diagnosis of COPD and lung cancer.

John Repine, M.D.

(Professor, WWRI)

Adult Respiratory Distress Syndrome (Clinical)
Inflammatory Lung Disease (Non Asthma)
Oxidant Lung Injury/Acute Lung Injury
Sepsis

Our research encompasses investigation of the mechanisms responsible for and the consequences of alterations in oxidant antioxidant balance. There is heavy emphasis on the role of inflammation and antioxidant defense processes. This research relates to ALI, ARDS and other inflammatory disorders.

David Riches, Ph.D.

(Professor, NJMRC)

Inflammatory Lung Disease (Non Asthma)
Interstitial Lung Disease

Our laboratory is pursuing questions about the cell biology of pulmonary inflammation and fibrosis. Through integrated basic and translational approaches and cutting edge techniques, we are investigating the mechanisms that lead to myofibroblast accumulation in pulmonary fibrosis. Specific areas of interest include: (i) investigating the biochemical mechanism underlying impaired myofibroblast apoptosis in pulmonary fibrosis, (ii) understanding the mechanisms of TNF-a signaling in the sensitization of myofibroblasts to Fas-induced apoptosis, (iii) determining the function of TRUSS, a novel TNF-receptor associated protein in TNF-a signaling and (iv) integration of these interests into translational studies aimed at furthering understanding of disease development in humans.

Cecile Rose, M.D.

(Associate Professor, NJMRC)

Environmental and Occupational Lung Disease

My research focuses on occupational and environmental lung diseases including hypersensitivity pneumonitis and other granulomatous disorders, the pneumoconioses, and occupational airways diseases. Epidemiologic and translational research includes investigation of the genetic and exposure variables associated with risk for laboratory animal allergies; recognition and prevention of hypersensitivity pneumonitis, particularly from exposure to bioaerosols such as nontuberculous mycobacteria; and risk factors for lung function and imaging abnormalities in coal, metal and non-metal miners.

Milene Saavedra, M.D.

(Assistant Professor, UH)

Cystic Fibrosis
Airways diseases
Sinus disease

I am focused on host pathogen interactions in airway epithelial cells, looking specifically at Pseudomonas aeruginosa virulence factors' effect on intracellular signaling in airway cells. I am particularly interested in how airway epithelial cells maintain homeostasis and how this balance is lost in severe airways inflammatory diseases. Additionally, we are testing biomarkers for responses to CF therapies, as well as characterizing differences between CF and non-CF sinus pathology.

Marvin Schwarz, M.D.

(Professor, UH, NJMRC)

Inflammatory Lung Disease (Non Asthma)
Interstitial Lung Disease

Clinical studies in interstitial lung disease particularly pulmonary fibrosis, the bronchiolitides, and the connective tissue diseases and diffuse alveolar hemorrhage. Mechanisms of fibroproliferation and novel therapies are stressed utilizing clinical material.

Philip L. Simonian, MD

(Assistant Professor, UCD)

Granulomatous Lung Disease
Inflammatory Lung Disease (Non-Asthma)
Interstitial Lung Disease
Lung Immunology

The focus of our research is the mechanisms by which T lymphocytes accumulate in the lung and promote pulmonary fibrosis in response to exposure to microbial antigens. We have developed a new murine model of hypersensitivity pneumonitis and pulmonary fibrosis to investigate how different T cell populations either promote or protect against the development of fibrotic lung disease induced by chronic exposure to a microbial pathogen.

E. Rand Sutherland, M.D., MPH

(Assistant Professor, NJMRC)

Asthma
COPD

Our lab focuses on clinical and translational research in asthma and COPD. We are a center in the NIH-sponsored Asthma Clinical Research Network, and other additional areas of research include investigation of biomarkers of prognosis and drug responsiveness in COPD, development of noninvasive measures of airway inflammation in asthma and COPD, evaluation of the role of infection in the pathogenesis of asthma and investigation of mechanisms governing the association between obesity and asthma.

Jeff Swigris, DO, MS

(Assistant Professor, NJMRC)

Interstitial lung disease

Dr. Swigris's research interests include conducting clinical studies and trials of therapeutic agents in patients with various interstitial lung diseases (ILD), including patients with ILD associated with underlying connective tissue disease. His current research program also includes developing a disease-specific instrument to assess quality of life in patients with idiopathic pulmonary fibrosis (IPF).

Laimute Taraseviciene-Stewart, PhD

(Assistant Professor, PHC)

Pulmonary Vascular Disease
Molecular/Cellular Pathogenesis of Severe Pulmonary Hypertension (SPH)
Immune mechanisms in Pathobiology of COPD/Emphysema

Endothelial cell (EC) dysfunction plays an important role in vascular remodeling and the development of severe pulmonary hypertension (SPH). My research interest explores the balance of EC death and proliferation, survival signals provided by Vascular Endothelial Growth Factor (VEGF) and VEGF receptors (R1 and R2) in animal models of SPH. We recently developed a novel animal model of autoimmune emphysema and showed for the first time that humoral- and CD4+ cell-dependent mechanisms are sufficient to trigger the development of emphysema, suggesting autoimmune mechanisms of alveolar septal cell destruction. We make use of our animal models of SPH and emphysema to search for new therapeutics to treat human diseases.

William Vandivier, M.D.

(Assistant Professor, NJMRC)

Inflammatory Lung Disease (Non-Asthma)

My research focuses on mechanisms regulating resolution of inflammation in the lung through clearance of apoptotic cells. Inflammatory cells dying by apoptosis facilitate the resolution of inflammation by sequestering toxic intracellular contents and by marking themselves for removal by phagocytes (an anti-inflammatory process). The contribution of specific mechanisms (i.e., collections, phosphatidyl serine receptor and ABC-cassette proteins) is studied using a combination of in vitro systems, knockout mice and patients with chronic inflammatory diseases.

Norbert Voelkel, M.D.

(Professor, UH, DL, PHC)

Pulmonary Vascular Disease
(Clinical, Molecular & Cellular Pathogenesis of Pulmonary Hypertension, Right Heart Failure)
Inflammatory Lung Disease (Non Asthma)
Adult Respiratory Distress Syndrome (Clinical)
Pathology of COPD, Emphysema

The lung vasculature is an important participant in the pathogenesis of many acute and chronic lung diseases (including COPD and ILD). Endothelial cell dysfunction and proliferation (manifestations of an altered phenotype) are pathogenetically important and part of vascular remodeling. Gene expression patterns can be studied in the tissue from patients with pulmonary hypertension and COPD (functional genomics approach) in order to improve our understanding of the pathobiology of these chronic diseases and to identify rational new drug targets.

Dennis Voelker, Ph.D.

(Professor, NJMRC)

Asthma
Epithelial Cell Biology
Lung Immunology
ARDS

The research in my laboratory is focused on:

• Biochemical regulation of pulmonary surfactant synthesis, recycling and secretion.
• Structure function analysis of surfactant proteins by site directed mutagenesis.
• The role of surfactant components in regulating innate immunity in the lung.
• Mechanisms of interorganelle transport of phospholipids.

David Wagner, Ph.D.

(Assistant Professor, WWRI)

Asthma Inflammatory Lung Disease (Non-Asthma) Pulmonary Vascular Disease

We have identified a unique T cell population that is clinically responsible for autoimmunity. These T cells are characterized as CD4+CD40+. They occur normally as a small percentage of the overall T cell compartment in healthy individuals but at greatly increased numbers in autoimmunity. We show in both mouse and human disease models that these T cells are highly auto-aggressive. We are focused on how to silence the aggressor component of these T cells through appropriate mechanisms of tolerance including TCR revision, altering the T cell receptor and thus altering antigen specificity and induced cell death. Our studies are determining that these T cells are pre-eminent not only in type 1 diabetes and rheumatoid arthritis but also in asthma, and other forms of COPD as well as causing vascular complications.

John Weil, M.D.

(Professor, UH, CVP)

Adult Respiratory Distress Syndrome (Clinical) Control of Breathing Oxidant Lung Injury/Acute Lung Injury Pulmonary Vascular Disease

Ventilatory control

Carotid body hypoxic sensing

Vascular biology in acute injury

Carolyn Welsh, M.D.

(Professor, DVAMC)

Venous Thrombosis / Pulmonary Vascular Disease

Vascular Lung Disease

I am seven years along in an epidemiologic study looking at genetic, clinical and acquired risk factors for venous thrombosis. We have enrolled one thousand subjects and have started risk stratification analyses in venous thromboembolism. I have also interested in investigating the role of hypercoagulability, and abnormalities of fibrinolysis in the pathophysiology of primary and secondary pulmonary hypertension, and COPD.

Sleep disorders

I am supervising two junior investigators in clinical projects in sleep medicine using a state of the art sleep laboratory. One project focuses on mechanisms of sudden death in epilepsy.

James West, Ph.D.

(Assistant Professor, CVP)

Pulmonary Vascular Disease

We primarily research idiopathic pulmonary arterial hypertension (PAH) using inducible transgenic mouse models, which replicate human patient family mutations in BMPR2. Our central hypothesis is that BMPR2 mutations do two things; through SMAD signaling, they result in de-differentiation of pulmonary vascular smooth muscle, and through MAPK signaling, they result in inability to properly regulate cell-mediated inflammatory reactions. In the context of a second hit in humans, this leads to abnormal recruitment of circulating progenitor cells, resulting in pulmonary vascular structural changes. We use transgenic mouse models, cardiac catheterization in mice, immunohistochemistry, siRNA in cell culture, and quantitative RT-PCR, among other methods, to test these hypotheses.

Marilee Wick, Ph.D.

(DVAMC, UH, CVP)

Neoplastic Lung Disease
Pulmonary Vascular Disease

Structural remodeling of the pulmonary vasculature in chronic hypoxic pulmonary hypertension. Cellular and molecular mechanisms regulating vascular cell proliferation in response to hypoxia, mechanical forces and growth factors. Early detection of lung cancer.

Robert A. Winn, M.D.

(Assistant Professor, DL, DVAMC)

Neoplastic Lung Disease

Over the last several years it has been discovered that genes important in developmental biology have also played a role in tumorigenesis. One such development pathway is the WNT pathway. It has been implicated in the oncogenic activity of a number of tumor types including: colon, breast, hepatocellular, as well as other tumor types. Our laboratory investigates the potential role of the WNT pathway in lung tumorigenesis. We pay particular attention to the signaling transduction of this pathway as well as that of the MAPK/JNK and the Eicosanoid pathways.

G. Scott Worthen, M.D.

(Professor, NJMRC)

Adult Respiratory Distress Syndrome
Inflammatory Lung Disease (Non Asthma)
Interstitial Lung Disease
Oxidant Lung Injury/Acute Lung Injury
Sepsis

The lung is the site of unique inflammatory responses that contribute to the pathogenesis of ARDS, ILD, and other important illnesses. Our laboratory is focused on mechanisms of leukocyte recruitment to the lung microcirculation in response to endotoxin, alteration in leukocyte mechanical (cytoskeletal) and adhesive properties, and the signals involved in transduction of a response from cellular receptors to biological effects. The neutrophil, despite its limited repertoire of synthetic functions, nonetheless retains exquisite sensitivity to stimuli in the local environment. The goal of the laboratory is to determine the nature of these signals and the mechanisms whereby specificity is maintained. Although human neutrophils are the primary tool, murine systems and engineered cellular models are employed.

Richard Wright, Ph.D.

(Associate Professor, WWRI)

Oxidant Lung Injury/Acute Lung Injury Respiratory Physiology

Oxygen based free radicals contribute to pathology in many ways, and I have been engaged in two projects united by my interest in the genetics of free radical synthesis. The first of these projects reflects a long-standing interest in how cellular mitochondria produce free radicals. It has been known for several decades that mitochondria are a primary source of free radicals in most cells, and these have been linked to cancer, inflammation, and many other disorders. We have taken advantage of the genetics of the brewing yeast Saccharomyces cerevisiae for these studies. With yeast, we have been able to study directly the genes involved in electron transport and free radical synthesis. We published extensively on the mechanisms by which glucose, oxygen, and cell growth regulate the activity of mitochondrial electron transport genes and free radical formation. Current studies will determine how mitochondria derived intracellular free radicals contribute to cell growth, development, and death. My second project has focused on the family of mammalian molybdenum iron-sulfur flavoproteins genes that are also sources of intracellular metabolic oxygen derived free radicals. This family of genes encodes the enzymes aldehyde oxidase, sulfite oxidase, and xanthine oxidodreductase (xanthine oxidase/dehydrogenase). Previous studies suggested a role for xanthine oxidoreductase in oxidative stress induced injury in ischemia/reperfusion and in inflammatory disorders. However, current analyses have revealed the far more subtle role in free radical signaling. Knockout genetics of xanthine oxidoreductase has demonstrated its physical and regulatory interaction with cyclooxygenase-2 and have confirmed the role of xanthine oxidoreductase in intracellular free radical signaling in inflammation and in the mammary gland. We have cloned, mapped, and determined the structure of several members of this family and have uncovered dramatic similarities in the sequences and structures of the genes for all these enzymes. Working with colleagues from several different institutions we have developed a picture of the organization of the human molybdenum hydroxylase genes on chromosome 2. These observations have linked the molybdenum iron-sulfur flavoproteins genes to several human diseases. Current analyses are focused on the mechanisms by which these enzymes mediate intracellular free radical signaling. Two models are presently in use. In one, the contribution of intracellular free radical signaling to lung inflammation is being studied in inflammatory leukocytes. In the other, the dramatic contribution of xanthine oxidoreductase to differentiation in the mammary epithelium is being studied for its role in malignant transformation and breast cancer. Our future plans will continue to develop an understanding of the mechanism by which oxygen regulates mitochondrial electron transport genes, and we will expand our understanding of free radical based intracellular signaling by the molybdenum iron-sulfur flavoproteins in breast and lung cancer where these enzymes may be playing a significant role.

Martin Zamora, M.D.

(Professor, UH, CVP)

Pulmonary Vascular Disease Lung Transplantation Lung Volume Reduction Surgery

My research has focused on translational research in the area of lung transplantation and lung volume reduction surgery. I have been interested in mechanisms of acute lung injury following lung transplantation and testing various agents to limit the degree of ischemia-reperfusion injury. Our group is also interested in the role of respiratory viruses in acute and chronic lung allograft rejection. Collaborative projects are also underway with immunologists and several labs in the division. The lung transplant program has served as a source of tissue and cells for various translational research projects in the division. I am also involved with studies regarding the cardiopulmonary changes that occur with and without exercise following lung volume reduction surgery.