2006 ATS Research Grant Recipients

Partnership Grants:

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

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

Harvey O. Coxson, PhD

University of British Columbia
Research: “Quantification of Post-transplant Bronchiolitis Obliterans Syndrome Using CT Scanning”

Dr. Coxson will determine whether CT scanning is useful for the identification of bronchiolitis obliterans (BO) in lung transplant recipients, which is the major long-term complication of lung transplantation. Lung transplantation has become an important treatment option for certain carefully selected patients with alpha-1 antitrypsin deficiency. BO affects over half of lung transplant patients and presents as progressive shortness of breath and is usually first identified using pulmonary function tests. CT scanning is a non-invasive, repeatable test which may be useful for identifying BO at a very early stage, when treatment may have the greatest likelihood of success.

Darrell N. Kotton, MD

Boston University
Research: “Stem Cell-based Therapy for Alpha-1 Antitrypsin Deficiency”

Dr. Kotton is working to develop a novel stem cell-based therapy for alpha-1 antitrypsin (AAT) deficiency. He will use lentiviral-mediated transfer of the normal human AAT gene into hematopoietic stem cells, or novel candidate liver progenitor populations, and then transplant these cells into mice in order to achieve stable and therapeutic secretion of AAT protein in lung tissue. If successful, this new approach could undergo safety testing and then be moved into future clinical trials of therapy for individuals afflicted with AAT deficiency.

ATS/American Society of TransplantationPartnership Grants in Transplantation

• Co-funded by the ATS and the American Society of Transplantation

Stavros Garantziotis, MD

Duke University
Research: “The Role of Innate Immunity in Alloimmune Lung Injury After Transplantation”

Dr. Garantziotis is studying the role of the innate immune system in lung rejection after transplantation. This study represents as an important step towards a better understanding of the mechanisms that render the lung highly vulnerable to immune injury. The study will identify risk factors for post-transplant injury as well as provide information about how to modify immunosuppressive treatment. The results could lead to novel therapies to prevent lung rejection and improve the outcomes of patients who undergo lung transplantation.

ATS/ARDS Foundation Partnership Grant in ARDS

• Co-funded by the ATS and the ARDS Foundation

Renee D. Stapleton, MD, MSc

University of Washington; Harborview Medical Center
Research: “Anti-inflammatory Effects of n-3 Fatty Acids in Patients with Acute Lung Injury”

Dr. Stapleton is performing a phase II randomized controlled trial which is the first attempt to provide a sound scientific basis for n-3 fatty acid administration in patients with acute lung injury (ALI). This clinical trial will provide “proof of concept” using biologic endpoints that reflect lung inflammation and will also lay the groundwork for a larger trial of nutritional therapy for patients with ALI. Dr. Stapleton hypothesizes that n-3 fatty acids will reduce lung and systemic inflammation, reduce organ failure and show trends toward improvement in clinical outcomes in patients with ALI.

ATS/Foundation for Sarcoidosis Research Partnership Grants in Sarcoidosis

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

Richard F. Silver, MD

Case Western Reserve University
Research: “Abnormal TLR Responses in the Pathogenesis of Pulmonary Sarcoidosis”

Sarcoidosis is an inflammatory disease of unknown cause that can affect many organs of the body. The lungs are the most frequent site of disease. Currently, the main treatment for sarcoidosis is the administration of anti-inflammatory corticosteroids. This treatment is frequently effective, but because it is not specific, it can lead to many unwanted and harmful side effects. Dr. Silver will investigate how white blood cells from the lungs of sarcoidosis patients recognize bacterial products using Toll-like receptors (TLR). If the proposed studies show that TLR responses of lung cells of patients with sarcoidosis are excessive, new treatments could be developed based on modifying TLR function. This could result in new approaches to treating patients with sarcoidosis.

Jan A. Wahlström, MD, PhD

Karolinska Institutet
Research: “Antigen Specificity in Sarcoidosis”

Sarcoidosis is a chronic inflammatory disease of unknown origin which affects the lungs and other organs. The T cells are the cells of the immune system that are believed to be central for initiating and maintaining the inflammation. Dr. Wahlström has identified a distinct population of T cells in the lungs of a clinically and genetically well characterized group of patients. Dr. Wahlström hypothesizes that these T cells have recognized and proliferated in response to a specific “sarcoidosis antigen”. Dr. Wahlström and his associates have been able to identify small peptides that are presented to the T cells in the lungs of these patients. This collection of peptides provides a unique opportunity to identify a sarcoidosis antigen, which could lead to a new understanding about how the disease occurs.

ATS/The LAM Foundation Partnership Grant in LAM

• Co-funded by the ATS and The LAM Foundation

Arnold S. Kristof, MD

The Research Institute of the McGill University Hospital Centre
Research: “The Role of Protein Kinase Cδ in the Pathogenesis of Lymphangioleiomyomatosis”

Dr. Kristof’s studies will enhance our knowledge about why lymphangioleiomyomatosis (LAM) progresses, and how to treat patients with this important disease. LAM is a disease that causes destruction of the lungs, failure of the respiratory system and need for lung transplantation. LAM is caused by abnormal growth of smooth muscle cells, which leads to lung cysts and abdominal tumors. Dr. Kristof is using molecular and cellular biology techniques to understand how a signaling molecule called mTOR helps cells choose between increased growth and premature death. These ‘signaling switches’ could be exploited to promote the death of abnormal LAM cells. These molecular switches and potential therapies might also control abnormal smooth muscle growth in other lung diseases, such as asthma.

ATS/Pulmonary Hypertension AssociationPartnership Grants in Pulmonary Hypertension

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

Todd M. Bull, MD
University of Colorado Denver Health Science Center
Research: “The Role of Kaposi’s Sarcoma Herpesvirus (HHV-8) in the Development of Severe Pulmonary Hypertension”

Dr. Bull is investigating mechanisms by which HHV-8 contributes to the development of severe pulmonary hypertension. Severe pulmonary arterial hypertension (PAH) is a poorly understood disease with severe clinical consequences for those afflicted. The disease process of PAH is characterized by an abnormal growth of cells in the pulmonary arteries. The ability of HHV-8 to infect pulmonary microvascular endothelial cells has already been demonstrated. Dr. Bull will investigate the effect of this infection on the gene and protein expression of these cells as well as the effect on cell growth and cell apoptosis (programmed cell death). Dr. Bull will also explore a possible connection between HHV-8 infection and alterations in the bone morphogenic protein (BMP) pathway, a pathway recognized to be important in the development of pulmonary hypertension.

Xinqi Wu, PhD
Children’s Hospital Boston
Research: “Hypoxic Regulation of Bone Morphogenetic Protein (BMP) Signaling and the Role of Id1 in the Development of Pulmonary Hypertension”

Dr. Wu hypothesizes that the suppression of the signaling molecule, Id1, may cause increased growth and inhibition of apoptosis of human pulmonary artery smooth muscle cells, contributing to the development of pulmonary hypertension. Primary pulmonary hypertension (PPH) is a fatal disorder characterized by excessive growth of blood vessel cells in the lungs, resulting in narrowing of vessels and increased blood pressure in the lungs, followed by heart failure. Dr. Wu is investigating Id1 expression in hypoxic lungs of mice and the role of Id1 in cell cycle progression, proliferation, apoptosis and migration, processes underlying vascular remodeling. Dr. Wu’s studies will identify additional hypoxia-regulated BMP target genes, enhance our understanding of PPH pathogenesis and may lead to the identification of molecules that play a critical role in PPH and could be targets for therapeutic intervention.

Unrestricted Grants:

Shweta Choudhry, PhD

University of California, San Francisco
Research: “Whole Genome Association Study to Identify Asthma Related Genes in Puerto Ricans”

Of all the US populations, Puerto Ricans have the highest asthma prevalence, morbidity and mortality rates. Despite these dramatic differences in asthma morbidity and mortality, very little is known about the genetic factors that contribute to asthma in this population. Dr. Choudhry will use a genetic technique called admixture mapping to try to identify genetic regions associated with susceptibility to asthma. Her studies will be the first application of this genetic technique in Puerto Rican populations. By gaining a better understanding of genetic factors which may be responsible for asthma among the Puerto Rican population, Dr. Choudhry’s findings could provide a way to identify individuals at high risk for morbidity and mortality from asthma.

Patricia J. Dubin, MD

Children’s Hospital of Pittsburgh
Research: “Type I and III IFNs in Pseudomonas Aeruginosa Pneumonia”

Dr. Dubin is studying P. aeruginosa, a type of bacteria that causes pneumonia, pulmonary damage and death in immunocompromised individuals and patients with cystic fibrosis. Current therapies against P. aeruginosa infection are inadequate, often targeted only at killing the bacteria. It has been determined that two chemicals the host makes, IL-23 and IL-17, are critical to fighting P. aeruginosa infection. IL-23 triggers the production of IL-17 and the recruitment of white blood cells that fight the infection. It is unclear how IL-23 production is regulated, but preliminary studies suggest that a group of signaling chemicals called interferons play a significant role in this. Preliminary studies show that type I interferons down-regulate IL-23 production and inflammation but that type III interferons actually up-regulate pro-inflammatory cytokines. Dr. Dubin will study whether manipulating interferon levels could change the host’s response to P. aeruginosa, and her work could lead to new treatments to help prevent lung damage from bacterial infection.

William E. Lawson, MD

Vanderbilt University Medical Center
Research: “Defining the Origins of Effector Fibroblasts in Pulmonary Fibrosis”

Idiopathic pulmonary fibrosis (IPF) is a severe lung disease in which patients develop the insidious onset of shortness of breath, decreased exercise capacity, scarring in the lung tissue and difficulty with oxygen exchange. Once diagnosed, the outcome in most IPF patients is gradual progression to respiratory failure and death within a period of three to five years. Dr. Lawson is studying what proportion of new lung fibroblasts arise from cells in the bone marrow and what proportion arise from cells in the lungs. A better understanding of the origins of fibroblasts would allow physicians and scientists to identify specific targets that could lead to new therapeutic strategies to limit progression of disease in IPF and other forms of lung fibrosis.

Hara Levy, MD

Brigham and Women’s Hospital; Children's Hospital Boston
Research: “IL –1 Gene Family Polymorphisms and Susceptibility to P. Aeruginosa in CF Patients”

Dr. Levy is studying why some people with cystic fibrosis (CF) develop very severe lung disease at an early age, while others have milder lung disease into adulthood. Progressive pulmonary disease associated with chronic bacterial infection and airway inflammation is the major cause of morbidity and mortality in cystic fibrosis (CF). CF lung disease is characterized by chronic infection by Pseudomonas aeruginosa. The basis for chronic infection is unknown, but both host and bacterial factors are likely to contribute. Dr. Levy hypothesizes that genetic variations may account for the differences in clinical course among patients with CF. The results of this study could eventually help to improve the treatment of patients with CF.

Jingsong Xu, PhD

Brigham and Women’s Hospital
Research: “Role of Lysyl Oxidases (LOX and LOXL1) in Normal Lung Development”

Dr. Xu is studying two proteins called LOX and LOXL1 that are important for matrix production during lung maturation. Lung maturation is a developmental process in which fetal and neonatal lungs develop open air spaces and get ready for gas exchange. This process is interrupted in premature babies. As a result, premature babies often develop breathlessness and hypoxia, which can be lethal. Dr. Xu’s studies are aimed at understanding the regulation of the normal lung maturation process and using the normal regulators of development to promote lung maturation in adult patients. Studying the processes regulated by these two enzymes may lead to new ways to promote normal matrix production and lung maturation.