2008 ATS Research Grant Recipients

Partnership Grants:

ATS/Alpha-1 Foundation Partnership Grant in Alpha-1 Antitrypsin Deficiency

• Co-funded by the ATS and the Alpha-1 Foundation

Shivraj S. Tyagi, PhD

Brigham and Women’s Hospital, Harvard Medical School
Research: “The Role of Bronchio-Alveolar Stem Cells in Cigarett- Smoke-Related Emphysema”

Chronic obstructive pulmonary disease (COPD) is a complex lung disease that is characterized by a gradual loss of lung function. It has been suggested that prolonged cigarette smoke (CS) exposure may add to the total burden of environmental factors that become sufficient to cause chronic airway/parenchymal disease like COPD. A greater understanding of novel pathways contributing to maintenance and repair of lung is needed. A recent study has revealed the existence of progenitor/stem cells in the lung capable of repairing the airway and airspace.
Dr. Tyagi and research colleagues have developed a mouse model which identified a specific protein, peroxisome proliferator-activating (PPAR)-γ, increased susceptibility to development of emphysema in response to chronic CS exposure. They will directly assess the necessity of these stem cells and PPARγ for lung repair in animals exposed to cigarette smoke. Their findings may identify novel targets and allow them to apply this knowledge to the treatment of human COPD patients.

ATS/Asthma and Allergy Foundation of America Partnership Grant in Asthma

• Co-funded by the ATS and the Asthma and Allergy Foundation of America

Njira L. Lugogo, MD

Duke University Medical Center
Research: “Obesity and Asthma: Modulation of Inflammation by Adipokines and the Effect of Weight Loss”

The ongoing obesity epidemic is unlikely to improve in the near future. Greater than 30 percent of adults over the age of 20 years old are obese. Multiple epidemiologic studies have demonstrated an increased risk of asthma associated with obesity. The reason for this increased risk is unknown and many theories exist about the effect of obesity on asthma. Adipose tissue (fat cells) produces inflammatory hormones that circulate in the blood and cause inflammation and disease in various organs, resulting in diseases like diabetes and coronary artery disease. The role of these hormones in asthma, particularly their effects on the severity of asthma and response to treatment, is unclear. The goal of Dr. Lugogo’s study is to determine how these hormones affect human asthma. Dr. Lugogo and are specifically interested in how these inflammatory hormones change with weight loss and how weight loss affects asthma control and severity.

ATS/Coalition for Pulmonary Fibrosis Partnership Grant in Pulmonary Fibrosis

• Co-funded by the ATS and the Coalition for Pulmonary Fibrosis

Andrew M. Tager, MD

Massachusetts General Hospital
Research: “Roles of the Novel Mediator LPA and its Receptor LPA1 in Pulmonary Fibrosis”

Idiopathic pulmonary fibrosis (IPF) is associated with unacceptably poor outcomes, but the biological processes driving this devastating disease unfortunately remains enigmatic. Recent evidence indicates that recurrent injury to the lungs, and abnormalities in the processes that repair injured tissues, contribute to IPF. Dr. Tager and his collaborators have identified a molecule, lysophosphatidic acid (LPA), which appears to be central to fibrosis developing after tissue injury. LPA exerts its actions through several receptor molecules, and they have been studying one of these, LPA1. They have found that mice genetically lacking LPA1 are dramatically protected from fibrosis in a model of IPF. Their goals are: (1) to determine how LPA and LPA1 work to control the development of fibrosis in our mouse IPF model; and (2) to determine whether LPA and LPA1 similarly control the development of fibrosis in human IPF. They believe that LPA and LPA1 represent exciting new targets for drug design for IPF.

ATS/Cystic Fibrosis Foundation Partnership Grant in Cystic Fibrosis

• Co-funded by the ATS and the Cystic Fibrosis Foundation

Lucas R. Hoffman, MD, PhD

Children’s Hospital and Regional Medical Center, University of Washington
Research: “The Impact of S. Aureus Normal and SCV Forms in Cystic Fibrosis Lung Disease”

People with cystic fibrosis (CF) have chronic lung infections that lead to irreversible lung damage. Substantial progress has been made in treating CF lung disease using antibiotics targeting Pseudomonas aeruginosa, a pathogen commonly cultured from these patients. Nevertheless, CF lung disease is not halted by antipseudomonal antibiotic treatment. The airways of CF patients are usually infected with multiple species of microbes, and the roles of species other than P. aeruginosa are poorly defined. Preliminary evidence suggests that the role of Staphylococcus aureus in CF lung disease has been underestimated. P. aeruginosa and S. aureus interact on the molecular level, rendering S. aureus difficult to detect and resistant to commonly used antibiotics. Dr. Hoffman plans to define the role of S. aureus, and its interaction with P. aeruginosa,in driving CF lung disease. This approach departs from current concepts of CF pathogenesis, and may suggest novel treatments for many chronic infections.

ATS/Foundation for Sarcoidosis Research Partnership Grants in Sarcoidosis

• Co-funded by the ATS and the Foundation for Sarcoidosis Research

Edward S. Chen, MD

The Johns Hopkins University
Research: “The Role of the Receptor for Advanced Glycation End-products in Sarcoidosis”

Sarcoidosis is a systemic inflammatory disorder associated with well-formed tiny nodules called granulomas that develop in different parts of the body, involving the lungs in over 90 percent of patients. Recent studies have shown that genetic variations of the receptor for advanced glycation end-products (RAGE) may be associated with an increased risk of developing sarcoidosis. Dr. Chen and his colleagues have identified that RAGE and a protein that stimulates RAGE, called serum amyloid A (SAA), are found in abundance in sarcoidosis. They will test whether RAGE and proteins that bind to RAGE, such as SAA, alter granuloma development in an experimental model of sarcoidosis. Using white blood cells from sarcoidosis patients, they will also determine whether RAGE stimulation causes a release of inflammatory chemicals that are important in granuloma development. These studies may lead to newer, safer treatments by helping to determine whether drugs that target RAGE might be beneficial in sarcoidosis.

Elliott D. Crouser, MD

The Ohio State University Research Foundation
Research: “Modulation of Pulmonary Sarcoidosis by Nicotinic Acetylcholine Receptors”
Partial funding for this grant was provided by a generous grant from the Nathan Cummings Foundation.

Research studies have shown that nicotine strongly suppresses the immune system and reduces the type of inflammation that is characteristic of sarcoidosis in the lungs. This study will determine if nicotine treatment, administered in the form of a skin patch, will reduce the severity of lung disease and improve the quality of life of patients with sarcoidosis. Specifically, it is hypothesized that nicotine treatment will reduce the severity of sarcoidosis symptoms, improve lung function, and resolve lung inflammation. If this hypothesis is proven to be correct in this relatively small group of patients, additional studies will be performed in a larger group of patients. If nicotine is ultimately found to be an effective treatment for sarcoidosis, it may replace some of the existing treatments which are frequently ineffective and have unacceptable side effects.

ATS/The LAM Foundation Partnership Grant in LAM

• Co-funded by the ATS and The LAM Foundation

Elena A. Goncharova, PhD

University of Pennsylvania
Research: “Defining the Role of RhoA GTPase in Modulating LAM Cell Growth”

Pulmonary lymphangioleiomyomatosis (LAM) is a fatal lung disease affecting primarily women of childbearing age. Abnormal growth of smooth muscle-like cells leading to the cystic destruction of the lungs is a manifestation of LAM disease. Under the mentorship of Vera Krymskaya, PhD, research associate professor of medicine at the University of Pennsylvania, Dr. Goncharova demonstrated that mutational inactivation of tumor suppressor tuberous sclerosis complex 2 (TSC2) with hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) and demonstrated that mTOR inhibitor rapamycin attenuated LAM cell growth. Their new data show that RhoA GTPase activity is up-regulated and contributes to abnormal LAM cell proliferation. Importantly, combined targeting of mTORC1 by rapamycin and RhoA by simvastatin, a clinically approved drug, abrogates TSC2-related cell and tumor growth; however, the cellular and molecular mechanisms of this inhibition are unknown. The goal of their study is to determine the role of RhoA in LAM cell proliferation and to investigate the benefits for the combined treatment of TSC2-null tumors with rapamycin and statins.

ATS/Pulmonary Hypertension Association Partnership Grants in Pulmonary Hypertension

• Co-funded by the ATS and the Pulmonary Hypertension Association

Kewal Asosingh, PhD

Cleveland Clinic Foundation
Research: “Role of Pulmonary Vascular Wall Resident Endothelial Progenitors and Circulating Bone Marrow-derived Angiogenic Precursors in Idiopathic Pulmonary Arterial Hypertension”

Despite intensive research, idiopathic pulmonary arterial hypertension (IPAH) is poorly understood and remains an incurable disease. Dr. Asosingh and his research colleagues’ preliminary studies suggest that the blood vessels within the lungs of patients with IPAH harbor endothelial stem cells with a high-growth capacity. Their research findings also identify that patients have high levels of circulating bone-marrow derived cells that are able to stimulate blood vessel formation. Thus, these circulating angiogenic cells may play a role in the vascular remodeling that typically occurs in the lungs of patients with the disease. The identification of cellular mechanisms that contribute to the vascular abnormalities in IPAH will allow the design of novel therapeutic approaches that specifically target disease-causing cells.

Qing Lu, DVM, PhD

Brown University
Research: “TGF-Beta1 and Pulmonary Artery Hypertension”

Pulmonary artery hypertension (PAH) is a severe disease with an average survival of 2 to 3 years upon diagnosis. It can occur as a primary form with unknown cause or secondary to other conditions. PAH is characterized by elevation of mean pulmonary artery pressure due to occlusions in the small precapillary vessels. Plexiform lesion, characterized by abnormal endothelial cell growth, is a common pathologic change observed in PAH. PAH has been linked to dysfunction of transforming growth factor (TGF)-beta1 signaling. Dr. Lu’s study will investigate if inhibition of ALK5, a TGF-beta1 type I receptor, causes plexiform lesion formation and PAH and understand the underlying mechanisms. The results from the proposed studies will provide novel insights into the role of TGF-beta1 signaling in modulation of PAH and may also provide novel therapeutic targets for PAH.

ATS/Respiratory Health Association of Metropolitan Chicago Partnership Grant in Asthma  

• Fully funded by the Respiratory Health Association of Metropolitan Chicago

Jerry A. Krishnan, MD, PhD

The University of Chicago
Research: “Repeated High-dose Inhaled CorticoSteroids for Acute Asthma (ReHICS) Study”

Severe acute asthma (a severe asthma attack) is a significant health and economic burden. Treatment with corticosteroids by mouth or vein and inhaled bronchodilators represent the cornerstone of conventional therapy for acute asthma. However, these treatments can take hours or days to provide benefits and some patients nevertheless develop respiratory failure. Dr. Krishnan’s proposed study will examine the effects of repeated high doses of inhaled corticosteroids (ICS) during severe acute asthma. Researchers at the University of Chicago under the obstructive lung disease program will enroll adults hospitalized for severe acute asthma at the University of Chicago Medical Center. Study participants will receive conventional medical therapy for severe acute asthma and either repeated high-dose ICS or placebo during a three-hour intervention period. They will measure and compare lung function, respiratory symptoms and markers of airway inflammation between treatment groups. Results will help examine the role of using repeated high doses of ICS as a new therapy to improve outcomes of severe acute asthma.

ATS/Boehringer Ingelheim Partnership Grants in Anticholinergic Research

• Made possible by a generous educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.

Pingfang Song, MD, PhD

Oregon Health & Science University
Research: “Choline Transport Can Specifically Target Non-neuronal Acetylcholine Synthesis”

Dr. Song has demonstrated that lung cells secrete acetylcholine (ACh) which functions as a locally acting hormone to stimulate growth of both normal cells and lung cancer cells. ACh synthesized by lung cells may also play an important role in asthma and COPD. Because ACh is also made in neurons in the brain and is critical for neuronal function, drugs that interfere with neural processing of ACh can be highly toxic. Thus, to develop therapeutic strategies that target non-neuronal ACh in the lung, a way to affect non-neuronal ACh without affecting neuronal Ach, must be developed. In preliminary studies they have determined that the mechanism of choline transport, the first step in ACh synthesis, differs between neurons and lung cells. This project will help to determine if non-neuronal ACh synthesis in the lung can be blocked by targeting specific choline transporters that do not affect ACh synthesis in neurons.

 

Cherry Wongtrakool, MD

Emory University School of Medicine
Research: “Prenatal Nicotine, Airway Reactivity and α7 Nicotinic Acetylcholine Receptors”

The epidemiologic link between maternal smoking and an increased incidence of wheezing and asthma in the offspring is well known. Nicotine, a major component of tobacco smoke, has effects on growth and development. Dr. Wongtrakool’s proposed research will explore the possibility that offsprings of maternal smokers are more prone to wheezing and asthma because the ability of nerves to respond to an irritant is altered due to changes in growth of the nerves and changes in the milieu of neural growth factors and inflammatory molecules. The laboratory’s aim to investigate how prenatal nicotine exposure, through signals mediated by the α7 nicotinic acetylcholine receptor, can affect the growth of nerves that innervate the airways and how neural growth factors can promote airway hyperresponsiveness through interactions with smooth muscle or inflammatory mediators. Their discoveries may provide innovative therapeutic targets to treat asthma or decrease the development of asthma in children of maternal smokers.

ATS/Respironics Partnership Grant in Sleep Disordered Breathing

• Made possible by a generous educational grant from Respironics Foundation

Sanjay R. Patel, MD, MS

Case Western Reserve University
Research: “Obstructive Sleep Apnea and Adipose Tissue Biology”

Obstructive sleep apnea is a common disease that increases the risk for heart disease and diabetes. One mechanism by which sleep apnea may cause these diseases is through effects on the activity of fat cells.

In this work, fat biopsies will be obtained from patients with sleep apnea before and after treatment. Levels of fat-related hormones that promote heart disease and diabetes will be measured in these biopsies to determine if these improve with treatment for sleep apnea. Levels of gene expression in the fat will also be measured to identify which genes have their expression altered with sleep apnea treatment. These results will help define how sleep apnea affects the function of fat cells. By understanding the pathways by which sleep apnea promotes development of heart disease and diabetes, it may be possible to identify new treatments that prevent complications from sleep apnea.

ATS Unrestricted Grants:

Vineet Bhandari, MD, DM

Yale University School of Medicine
Research: “Role of Angiopoietin 2 in Hyperoxia-Induced Lung Injury in the Newborn”

Many premature newborns (NB) require high concentrations of oxygen (hyperoxia) to survive, but this therapy often results in lung injury and culminating in bronchopulmonary dysplasia (BPD). BPD has now become the most common chronic lung disease of infants in the US. One mediator of hyperoxia-induced lung injury is Angiopoietin 2, as reported by Dr. Bhandari and his colleagues earlier.
They have also shown that Angiopoietin 2 concentrations are markedly increased in the airway secretions of premature human NB babies who develop BPD. Now, Dr. Bhandari and colleagues seek to understand how Angiopoietin 2 causes hyperoxia-induced injury in the NB lung. Since there are crucial developmental differences in the response of the NB lung to hyperoxia (compared to the adult) and hyperoxia-induced lung injury in the human adult does not lead to BPD, it is critical to independently understand this process in the developing lung. This can pave the way for appropriate therapeutic options in human BPD.

Maria Antonieta Guerrero-Plata, PhD

The University of Texas Medical Branch
Research: “Pulmonary Dendritic Cells and Impaired T Cell Responses in Viral Bronchiolitis”

Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infections (LRTI) in infants and young children. A vaccine against RSV has not yet been developed and no specific therapy is available. Recent clinical observations have suggested that T lymphocytes, are virtually absent in lung tissue of fatal cases of RSV LRTI, suggesting that RSV may severely impact T cell immunity. However, the underlying mechanisms for this effect are not fully understood. In this work, Dr. Guerrero-Plata and research collaborators hypothesize that RSV infection is capable to drive airway dendritic cells to express a repertoire of cell-associated antigen presenting molecules with inhibitory function on T cells. Studies will be conducted in infants with naturally acquired RSV infections and in experimentally infected mice. The long-term goal of this work is to develop new strategies to boost antiviral immunity and long-lasting protection against RSV and other respiratory viral pathogens that cause significant airway morbidity.

Vibha N. Lama, MD, MS

University of Michigan
Research: “Role of Lung Resident Mesenchymal Stem Cells in Allo-Mediated Lung Injury”

Acute and chronic allograft rejection continues to be the major factor limiting successful long-term outcomes post-lung transplantation. The aim of this application is to study the role of a novel population of cells termed mesenchymal stem cells isolated from lungs in suppressing cellular components of allograft rejection. The studies proposed in this project will elucidate the role of lung-resident mesenchymal stem cells as an immune modulating cell in human lung allograft environment by utilizing cells isolated directly from human lung transplant recipients. The therapeutic potential of mesenchymal stem cells and their mechanism of action will be studied using pertinent rodent models of acute lung allograft rejection. This project will provide novel information regarding the salutary role of these progenitor/stem cells in lung allograft rejection and will lay the background for potential therapeutic approaches using mesenchymal stem cells in lung transplant recipients to treat and prevent rejection.

Mark R. Looney, MD

2008 Carl Booberg Research Awardee
University of California, San Francisco
Research: “The Contribution of Platelets to Experimental Acute Lung Injury”

Acute lung injury (ALI) is a syndrome that affects roughly 200,000 persons each year in the United States, with mortality of approximately 40 percent, and without a specific pharmacotherapy. Dr. Looney’s research project focuses on understanding the pivotal inflammatory events that lead to barrier disruption in ALI. The neutrophil has long been associated with the development of ALI, but it is his hypothesis that the platelet is also a critical mediator leading to lung microcirculatory damage. Experimental work will be done using strategies of platelet depletion and inhibition and by using specific genetic knockout mice that will probe the molecular interactions between platelets, neutrophils, and the endothelium. If platelets are found to be critical mediators of ALI, then a new area of potential therapies can be explored. The results of this investigation could lay the ground work for future phase I and phase II clinical trials of anti-platelet therapy in ALI.