Category: Pulmonary Development and Lung Disease

Pulmonary biology and disease


Stephen C Lazarus, M.D.

Lazarus

Research Interests:
Role of inflammation in asthma and COPD, mucus hypersecretion.

Summary:
Asthma affects 5-10% of the US population, and deaths from asthma have increased for several decades. COPD is the 4th leading cause of death in the US. Understanding the mechanisms involved in these diseases and how best to treat them will contribute to better outcomes.

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Laura L Koth, M.D.

KOTH_image

Research Interests:
Sarcoidosis Granulomatous Lung Diseases T cells Monocytes chemokines

Summary:
Dr. Koth’s research program is structured around the study of samples from human research studies. With the breath of research techniques that can be applied to human samples to learn about disease, Dr. Koth is taking a direct approach in the study of lung diseases. Dr. Koth’s current focus involves understanding the inflammatory disease called sarcoidosis. This is not a disease as common as asthma, but it affects both young and middle aged people and causes significant morbidity and mortality. More awareness and funds are needed if we hope to understand the complicated biology of the disease. For example, many of the main immune subsets of the body are abnormally regulated in this disease. Most research has focused on the traditional T-cell. For example, it is thought that specific T cells are very activated and making inflammatory products which are contributing to and continuing the disease. However there are other immune cells that have not been studied adequately. Dr. Koth’s lab has taken an active interest in these other types of immune cells. One reason for this is that we have identified, using Genomics research, that specific transcripts in the blood actually predict whether a specific patient will have progressive disease or not. She and her lab are now pursuing a line of investigation to understand where this ‘biomarker message’ is coming from in order to be able to stop it.

Dr. Koth’s lab is also interested in using state-of-the-art technology to think about new therapies for this disease. We are looking into cutting-edge translational methods of expanding a type of immune cell responsible for down regulating the inflammatory process of the body. To perform these experiments in clinical trials will require significant financial support and we are seeking this input in order to move this very exciting potential treatment forward. The other aspect of my research program includes the development of a ‘center of excellence in sarcoidosis’. This program will be designed to include both excellence in clinical care and novel clinical studies. Developing clinical care standards is an important area in managing sarcoidosis patients since sarcoidosis is a chronic disease that may be active for 10-20 years or more. Thus, a full-service clinical care program would facilitate the creation of clinical management tools and treatment regimens (developed as products from clinical trials networks) to address three arms of care in sarcoidosis: 1) organ damage, 2) symptom control, and 3) psychosocial aspects of living with the disease.

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Thomas B Kornberg, B.A., Ph.D.

Kornberg

Research Interests:
Developmental regulation

Summary:
My laboratory investigates the mechanisms that pattern developing organs. We carry out our studies on the fruit fly, as it offers many advantages with its ready accessibility to histological analysis and the ease with which genetic manipulations can be made. We focus on two systems  the fly wing and the fly lung. Both are model systems that offer opportunities to identify and characterize basic genetic and molecular mechanisms that are relevant to human development and disease.

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Samuel Hawgood, M.B., B.S., M.D.

Hawgood

Research Interests:
Structure and function of surfactant apoproteins

Summary:
Our research activity is focused on the biology of the pulmonary alveolus with a particular emphasis on the structure and function of the pulmonary surfactant apoproteins. The human lung is made up of some 500 million alveoli each with a diameter of 200 microns and a septal wall thickness of only 5-8 microns. The large surface area provided by this foam-like architecture is ideal for rapid respiratory gas exchange but necessitates some unique biological answers to the threat to structural stability posed by the problem of high surface tension and the constant exposure to environmental pollutants, allergens and microbes. Pulmonary surfactant, a lipoprotein secretion of the alveolar epithelial type II cell, stabilizes alveolar structure at low transpulmonary pressures by reducing the retractile surface forces that would otherwise act to collapse the lung at end expiration. The surfactant apoproteins also act as components of the pulmonary innate defense system protecting the lung from inflammation and infection.

A derangement of alveolar stability, secondary to a developmental deficiency of surfactant, is the major factor in the pathogenesis of the respiratory distress syndrome of the newborn (RDS). My interest in the biology of surfactant grew from clinical experience in neonatology where RDS is a major cause of neonatal death. I moved to UCSF in 1982 as a research fellow with Dr. John Clements, the scientist who discovered surfactant in the late 1950’s. He started his own laboratory, focused on the proteins associated with surfactant, in 1984. By 1985 our laboratory had identified three novel surfactant-associated proteins, now known as SP-A, SP-B and SP-C, and had derived their primary structures from full-length cDNA and genomic clones. In 1993, Erica Crouch in St. Louis described a fourth protein, SP-D. The higher-order structure, genetic regulation, metabolism, and function of these proteins have been the focus of our research since that time.
We now know that the surfactant proteins have important roles in the activity of surfactant, particularly the ability to rapidly spread phospholipids at the alveolar surface. The proteins also regulate surfactant turnover and metabolism in the alveolus and play a part in non-antibody mediated response to infection and inflammation in the alveolus. The biology of these proteins is complex and they apparently function as interacting hetero-oligomers to mediate their multiple effects on surfactant biology. At least two of the surfactant proteins, SP-B and SP-C, are present in exogenous surfactants approved for clinical use and fatal human disease has been linked to inherited mutations in both these proteins. This clear link to human disease provides a strong rationale to obtain a detailed understanding of their structure and function.

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Akiko Hata, Ph.D.

Hata

Research Interests:
Mechanisms of growth factor signaling in the control of cell growth and differentiation of vascular cells

Summary:
Research in the Hata lab focuses on the role of the BMP/TGF signaling pathway in the maintenance of vascular homeostasis, control of vascular injury repair, and pathogenesis of vascular diseases, including idiopathic pulmonary arterial hypertension (IPAH), hereditary hemorrhagic telangiectasia (HHT), restenosis, and atherosclerosis. Our approach is to study gene mutations identified among patients with IPAH or HHT and elucidate how these gene products affect the signaling pathway as well as vascular physiology using both cell culture and animal models.

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Michael Gropper, M.D., Ph.D.

Gropper

Research Interests:
Transfusion related acute lung injury, acute respiratory failure, acute respiratory distress syndrome, sepsis, ventilator associated pneumonia, resuscitation, mechanical ventilation, critical care outcomes

Summary:
My research interests are all focused on improving outcomes in critically ill patients in the ICU. These interests range from basic scientific questions regarding the mechanisms of harm from blood transfusions to asking about whether we efficiently utilize our precious resources, particularly at the end of life.

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Stanton A Glantz, Ph.D.

Glantz

Research Interests:
Mechanics of cardiac function (experimental and theoretical); environmental tobacco smoke and tobacco control policy

Summary:
Dr Glantz studies the effectiveness of different tobacco control strategies, particularly in the context of large state-run tobacco control programs, how the tobacco industry works to systematically distort the scientific process and animal and human studies of the effects of passive smoking on the heart.

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Jeffrey R Fineman, M.D.

Fineman

Research Interests:
Endothelial regulation of the pulmonary circulation during normal development and during the development of pediatric pulmonary hypertension disorders. Endothelial dysfunction in pediatric pulmonary hypertension

Summary:
Pulmonary hypertension, high blood pressure in the lungs, is a serious disorder in subsets of neonates, infants, and children. These include newborns with persistent pulmonary hypertension of the newborn (PPHN), children with congenital heart defects, and teenagers and young adults with primary pulmonary hypertension. The vascular endothelium (the cells that line the blood vessels in the lungs), via the production of vasoactive factors such as nitric oxide and endothelin-1, are important regulators of the tone and growth of pulmonary blood vessels. We utilize an integrated physiologic, biochemical, molecular, and anatomic approach, to study the potential role of aberrant endothelial function in the pathophysiology of pulmonary hypertensive disorders. To this end, we utilize fetal surgical techniques to create animal models of congenital heart disease, and investigate the early role of endothelial alterations in the pathophysiology of pulmonary hypertension secondary to congenital heart disease with increased pulmonary blood flow. Our clinical research interests include the use of pulmonary vasodilator therapy for pediatric pulmonary hypertension, and the use of peri-operative BNP levels as marker of outcome following repair of congenital heart disease.

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John Vincent Fahy, M.D.

Fahy

Research Interests:
Mechanism oriented studies of airway disease in human subjects

Summary:
Our research involves studies in people with airway diseases such as asthma, cystic fibrosis, and chronic bronchitis. We are involved in clinical trials of new and established treatments on the one hand and in clinical studies designed to improve understanding of mechanism of disease on the other. For clinical trials, we often collaborate with other CVRI investigators or investigators at other institutions to compare the efficacy of new and established drugs. In conducting clinical trials, we are usually interested in exploring the effects of drugs not just on measures of lung function but also on measures of airway inflammation and remodeling. For this purpose, our laboratory has developed expertise in measuring markers of inflammation and remodeling in samples of sputum or in samples of airway fluids and tissue collected during bronchoscopy. Our lab is particularly experienced in measuring gene expression using gene chips and PCR and in quantifying pathology using a rigorous method of quantitative morphology called stereology.

For our research on mechanisms of airway disease, we are particularly interested in abnormalities of airway epithelial cells (the lining cells of the airway) and in abnormalities in airway mucus. Mucus abnormalities are common in lung diseases, and we are interested in finding out the specific mucus abnormalities that are characteristic of different lung diseases such as asthma and cystic fibrosis. Recently, we have begun to explore the physical properties of airway mucus – thickness, stickiness, and adhesiveness – using an instrument called a rheometer. The rheology of airway mucus has not been investigated in detail, but the research resources of the CVRI are well suited to making progress in this area. For example, in our clinical laboratories in the CVRI, we can collect induced sputum from volunteers in a carefully controlled way, and in our bench laboratories we can make careful rheological measures. These rheologic measures are allowing personnel in our lab to explore new strategies for breaking up the mucus that normally clogs airways.

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David J Erle, M.D.

Erle

Research Interests:
Asthma, allergy and inflammation; functional genomics

Summary:
Asthma is an increasingly common disease that affects about 20 million American children and adults. We are working to understand how proteins made by the immune system act within the lungs to cause some of the most important problems experienced by people with asthma. We also work on understanding newly discovered ways in which genes are turned on and off during health and disease.

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Joanne N Engel, M.D., Ph.D.

Engel

Research Interests:
Bacterial Pathogen-Host Cell Interactions

Summary:
My laboratory is interested understanding and exploiting the complex interplay of microbial pathogens with eukaryotic cells. To that end, we have investigated the key processes of microbial attachment and entry, intracellular survival, and host cell injury in the context of two important human pathogens, Pseudomonas aeruginosa (PA) and Chlamydia trachomatis (CT). Each of these microorganisms has developed a unique strategy for successful survival that involves subverting and exploiting host cell pathways. Dissecting these processes will allow the development of new diagnostics, therapeutics, and vaccines and will provide a unique window into eukaryotic cell biology.

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