Partnership Grants:

ATS/Pfizer Research Grant in Pulmonary Arterial Hypertension

• Made possible by an educational grant from Pfizer, Inc.

Scott Halpern, MD, PhD
University of Pennsylvania
Research: “Enhancing the Efficiency of Randomized Clinical Trials of Novel Pulmonary Arterial Hypertension Therapies”

Pulmonary arterial hypertension (PAH) is a deadly disease for which treatments have only recently become available. Unfortunately, there are several barriers to conducting clinical trials of PAH therapies that could provide convincing evidence of the effects of new and existing therapies. The first barrier is uncertainty about how to best measure the effects of drugs. Traditionally, this has been measured using the distance walked in 6 minutes, but we need to better understand how well changes in walk distance predict changes in more meaningful outcomes such as quality and quantity of life. The second barrier is that we presently lack a way to predict which patients will respond to which therapies, making both research and practice less well-suited to optimizing outcomes for individual patients.  Third, although the most scientifically sound way to test new drugs is by comparing them with placebo, to do this safely and ethically requires that we first be sure that receiving placebo instead of active treatment for a brief period does not pose substantial risks to patients in the long run. This research uses data on nearly 2000 patients with PAH to overcome these barriers to the efficient conduct of clinical trials in PAH, thereby paving the way for the more rapid development of clinically valuable treatments for this devastating disease.

ATS/Alpha-1 Foundation Research Grant

• Fully funded by the Alpha-1 Foundation

Katsuyuki Takeda, MD, PhD
National Jewish Health
Research: “New Approaches to Tissue Repair of Pulmonary Emphysema”

The main clinical feature of alpha-1 antitrypsin deficiency is early onset emphysema associated with very poor prognosis in the absence of lung transplantation. Clinical studies with restorative treatments of alpha-1 antitrypsin have shown only marginal effects. The emerging technology of stem cell therapy, such as the administration of mesenchymal stem cells (MSCs), has been intensively studied in a variety of human diseases, including emphysema. In animal models of emphysema, the acid form of vitamin A (all-trans retinoic acid; ATRA) has been shown to have tissue repair effects by inducing cell differentiation. However, limited effects have been shown in humans. Dr. Takeda and colleagues propose to study combination treatments of MSCs and ATRA to repair tissue damage in emphysema. As MSCs have been shown to have both anti-inflammatory and tissue repair properties, combination treatment with ATRA is expected to have synergistic effects. Furthermore, they propose to explore the role of p70S6 kinase, which is a critical element for stem cell differentiation, in the repair process of lung tissue. These studies may provide novel therapeutic approaches for the treatment of emphysema.

ATS/Coalition for Pulmonary Fibrosis/Pulmonary Fibrosis Foundation Research Grants

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

Steven K. Huang, MD
University of Michigan
Research: “The Regulation and Pattern of the DNA Methylome in Pulmonary Fibrosis”

Epigenetic modifications, including methylation of DNA, are known to be important in cancer and lupus, but the role of these modifications in pulmonary fibrosis has only recently been explored. Select genes have been shown to be hypermethylated in fibroblasts of patients with pulmonary fibrosis, but whether other genes are hyper- or hypo-methylated is unknown. In this proposal, Dr. Huang and his colleagues will explore in a systematic fashion the methylation patterns of fibroblasts in fibrotic lung, with the purpose of determining the mechanism by which the antifibrotic mediator, prostaglandin E2, can regulate DNA methylation machinery. These studies will provide further insight into the role of DNA methylation in the pathogenesis of pulmonary fibrosis and into the mechanisms by which these epigenetic changes can be modified.

Erica Herzog, MD, PhD
Yale University
Research: “Semaphorin 7a and Alternative Macrophage Activation in Idiopathic Pulmonary Fibrosis”

Idiopathic pulmonary fibrosis (IPF) is a devastating disease in which gas exchange regions of the lungs are replaced by scar tissue. Despite many years of research into this disease, insight remains poor and patients with IPF progress inexorably to respiratory failure and an untimely death. An emerging area of interest in this field is the role that immune cells called alternatively activated macrophages (M2s) play in the development of IPF. Dr. Herzog and her colleagues’ studies show that M2s are associated with IPF. They have also found a novel role for Semaphorin 7a in the accumulation of M2 macrophages in the diseased lung in a mouse model of pulmonary fibrosis and increased levels of Semaphorin 7a in the blood of patients with IPF. Semaphorin 7a controls brain development and immune cell activation. There is no known link between Semaphorin 7a, M2s and IPF. Aim 1 of this proposal will determine the mechanism through which Semaphorin 7a promotes the appearance of M2s and collagen deposition in a mouse model of pulmonary fibrosis. Aim 2 will determine the mechanism through which Semaphorin 7a effects the differentiation and activation of M2s obtained from patients with IPF.

Philip Simonian

University of Colorado, Denver
Research: “Protection from Inflammation-Induced Pulmonary Fibrosis by IL-22”

Hypersensitivity pneumonitis (HP) is a lung disease caused by repeated exposure to inhaled particles. Chronic inflammation occurs in the lung of patients who are repeatedly exposed to a wide variety of inhaled particles, including bacteria such as Bacillus subtilis. In addition, chronic inflammation can cause scarring of the lungs or pulmonary fibrosis, which occurs in up to 41 percent of patients with HP and which results in irreversible lung dysfunction with a five-year mortality of 27 percent and median survival of 13 years. In a mouse model of HP induced by repeated exposure to the environmental microorganism, Bacillus subtilis, specific cells of the immune system called T cells express a molecule named IL-22, which suppresses the development of pulmonary fibrosis. The goal of this grant is to define the mechanism by which IL-22 protects the lung from chronic inflammation and fibrosis caused by repeated exposure to B. subtilis.

Beiyun Zhou, PhD

University of Southern California
Research: “Endoplasmic Reticulum Stress Induces Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells: Role in Pulmonary Fibrosis”

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder of unknown cause characterized by excessive scar tissue formation or fibrosis, which leads to lung destruction, abnormal gas exchange and ultimately death from inability to breath (respiratory failure). Recent evidence suggests that, in addition to activation of scar-producing cells (fibroblasts) that are normally present in the lung, fibroblasts can also arise through a process called epithelial-mesenchymal transition (EMT). In the course of EMT, epithelial cells lining the gas exchange surface of the lung change into fibroblasts in response to environmental stimuli. Endoplasmic reticulum (ER) stress is a condition in which cellular insults promote inappropriate folding of proteins in a part of the cell called the ER that can injure cells when excessive. ER stress has been implicated in death of the lining epithelial cells. Some also suggest it contributes to development of fibrosis in IPF. In this proposal, Dr. Zhou and colleagues will investigate the hypothesis that ER stress also induces EMT in epithelial cells directly contributing to fibrosis. Understanding the mechanisms whereby ER stress contributes to accumulation of scar tissue in pulmonary fibrosis should give insight into novel therapeutic strategies for management of patients with IPF and ways to decrease morbidity of this fatal disease.

ATS/COPD Foundation Research Grant

• Fully funded by the COPD Foundation

Derek Byers, MD, PhD
Washington University in St. Louis
Research: “12,15-Lipoxygenase Isoform Activities to Stratify COPD”

Chronic obstructive pulmonary disease is the only major cause of morbidity and mortality worldwide that is increasing in incidence, suggesting an urgent need of better methods for diagnosis and treatment. Ideally, these methods should target the pathological effects of immune cell activation, mucus production and airspace destruction that worsen with the severity of disease. Using a mouse model of chronic obstructive lung disease and then translational studies of humans with COPD and asthma, Dr. Byers and colleagues have found that alternatively activated, “M2,” macrophages produce high levels of IL-13 to mediate airway inflammation and associated mucous production. Preliminary data now indicate that 12,15-lipoxygenase isozymes in humans can potentially be used to discriminate M2 macrophage activity from airway changes that are associated with severe disease. In this project, the researchers will define the differences in 12,15-lipoxygenase enzyme expression and products in the lung tissues and sera from a large panel of patients with COPD and develop an assay that can help to better stratify disease.

ATS/Foundation for Sarcoidosis Research Grant

• Fully funded by the Foundation for Sarcoidosis Research

Kyra Oswald-Richter, PhD
Vanderbilt University Medical Center
Research: “The Role of Differential Cytokine Production in Sarcoidosis Disease Pathogenesis”

Striking disparities exist in sarcoidosis clinical outcome. Increased frequencies of CD4+ T cells in sarcoidosis bronchoalveolar lavage suggest that the strength of the immune response contributes to disease outcome. Dr. Oswald-Richter and colleagues propose to investigate the contribution of T cell biologic function to these observed disparities. They will identify mechanisms by which CD4+ T cells regulate disease outcome. The investigators will perform functional analysis of CD4+ T cells to determine if loss or gain of function correlates with disease outcome. Moreover, analysis of sarcoidosis subjects with good and poor prognoses will reveal cytokine patterns and T cell subset distribution to better prognosticate disease and potentially identify therapeutic targets.

ATS/Pulmonary Hypertension Association/Pfizer Research Fellowships in Pulmonary Arterial Hypertension
These research fellowships are made possible by fellowships from the Pulmonary Hypertension Association and Pfizer, Inc.

Laura E. Fredenburgh, MD

Brigham and Women's Hospital
Research: “Oncogene Mutation Profiling in Pulmonary Arterial Hypertension”

Pulmonary arterial hypertension (PAH) is characterized by abnormal growth of cells within the pulmonary artery wall, similar to cancer cells, which may lead to irreversible vascular remodeling, failure of the right side of the heart and death. Inherited genetic mutations in a protein called bone morphogenetic protein receptor 2 (BMPR2) have been found in 70 percent of familial and 10 to 30  percent of idiopathic PAH or IPAH patients. However, the chance that an individual with a mutation develops disease is only 10 to 20 percent and most patients with IPAH do not have one of these mutations. Dr. Fredenburgh and her colleagues hypothesize that spontaneous mutations occur in cancer genes in cells within the vessel wall of pulmonary arteries and promote uncontrolled growth of cells, leading to irreversible vascular remodeling and the development of clinical disease. The goal of their proposed study is to perform a rigorous genetic analysis of DNA isolated from the remodeled pulmonary arteries of PAH patients to determine if spontaneous mutations occur in genes linked to common cancers. Their research has the potential to identify new pathways for targeted therapy to prevent irreversible vascular remodeling, right heart failure and death in patients with PAH.

Tim Lahm, MD

Indiana University
Research: “Estrogen Metabolism and Autophagy in Hypoxic Pulmonary Hypertension”

Hypoxic pulmonary hypertension (HPH) is a frequent clinical problem leading to right heart failure and death. No pharmacologic treatments for HPH exist. Dr. Lahm and his colleagues have previously demonstrated that females exhibit less severe HPH than males; protection that is, at least in part, attributed to beneficial effects of 17beta-estradiol (E2). However, the exact mechanisms by which E2 exerts protection from HPH remain unknown. A better understanding may lead to targeted, non-hormonal therapies for HPH patients of either sex. Dr. Lahm and his colleagues have also demonstrated that inhibition of the conversion of E2 to certain metabolites further enhances the E2-mediated protection in HPH. One of the mechanisms by which E2 exerts protective effects is by inducing autophagy, a mechanism that enables cells to adapt to environmental stresses (e.g. hypoxia). While intuitively, the induction of autophagy is protective, its role in the pathogenesis of HPH has not yet been investigated. According to this rationale, the researchers propose that the protective effects of E2 on HPH are mediated by a metabolite-independent, autophagy-dependent mechanism, and are further enhanced by E2 conversion inhibitors.

American Lung Association of Oregon Grant

• Funded through a gift to the ATS Foundation

Andrew T. Lovering, PhD
University of Oregon
Research: “Prevention of Hypoxemia-Induced Intrapulmonary Arteriovenous Shunting in Patients with Chronic Obstructive Pulmonary Disease”

People with chronic obstructive pulmonary disease (COPD) are more susceptible to brain and heart injury caused by small clots (emboli) than people without COPD. These emboli in the blood are typically filtered out by the very small blood vessels in the lungs of healthy humans. Thus, it is not known why people with COPD are more susceptible to injuries like stroke and heart attack. Dr. Lovering and colleagues hypothesize that people with COPD are at an increased risk for these injuries because of large diameter pathways in their lungs that allow harmful emboli to get through the lung without being trapped. These large diameter pathways are called intrapulmonary arteriovenous anastomoses or shunts. The investigators’ previous research has shown that these shunts are closed at rest in healthy humans, but can be opened when oxygen levels in the blood are experimentally decreased. People with COPD have low blood oxygen levels because of their lung disease and therefore, may also have open shunts. The use of oxygen therapy to increase blood oxygen levels in people with COPD may be able to close these shunts. If this is true, then they could help reduce the risk of stroke and/or heart attacks in people with COPD.

ATS/Merck Translational Research Grant in Asthma

• Made possible by an educational grant from Merck

Akshay Sood, MD, MPH
University of New Mexico
Research: “Lung Adiponectin, Epigenetics and Asthma in Women”

Asthma and obesity are increasingly common in the United States. Obesity is a risk factor for asthma, particularly among women. Asthma has inflammatory and epigenetic bases. Adipose tissue produces proteins such as adiponectin that may have anti-inflammatory and epigenetic effects. Studies in mice show a protective role for adiponectin in asthma. This is supported by Dr. Sood and his colleagues’ human data that low serum adiponectin concentrations increase future risk for developing asthma only among women. Further, the murine model suggests that lung adiponectin differs from serum adiponectin and is possibly more relevant for the airway changes of asthma. Lung adiponectin has not been previously studied in humans. Thus, it is currently not known in humans whether lung adiponectin concentrations reflect serum adiponectin concentrations and whether lung adiponectin is associated with asthma-related physiologic and epigenetic changes in the airway. Studying the association between lung adiponectin and asthma outcomes may increase our understanding of the mechanistic basis for the adiponectin-asthma association. This may identify new approaches for preventing and treating asthma.

Additional grants will be announced as they are awarded.