2011 ATS Research Grant Recipients

Ferhaan Ahmad, MD, PhD, DCS
$25,000 (1 year)

• University of Pittsburgh
• Assistant Professor of Medicine and Human Genetics     
• Cardiovascular Institute

Grant Title: Applying Genomics as a Springboard to Novel Mechanisms of Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by abnormal thickening of blood vessel walls. Even with the best treatments, only about half of patients survive five years after diagnosis. This project will analyze the molecular and cellular pathways that different lung blood vessel cells follow to become abnormal in PAH, and identify new treatments that reverse these pathways and possibly cure patients. To accomplish this goal, we plan to study blood vessels from lungs removed from patients with PAH at the time they are undergoing lung or heart-lung transplant operations.

Mary Beth Brown, PhD, PT, ATC
$25,000 (1 year)

• Indiana University (Indianapolis)
• Assistant Professor
• Physical Therapy

Grant Title: Clinical Investigation of a Daily Walking Program plus L-Arginine Supplementation for the Treatment of Pulmonary Arterial Hypertension

We are investigating if functional and biochemical indicators of disease progression are attenuated in patients with pulmonary arterial hypertension (PAH) by 12 weeks of daily aerobic exercise plus dietary supplementation of L-arginine, an amino acid important to vascular health.  Training will consist of a simple walking program- 3 supervised treadmill sessions and 3 unsupervised home walking sessions per week at moderate intensity for 45 minutes. Supervised exercise and testing will be performed at the National Institute of Fitness and Sport (NIFS) on the IU School of Medicine campus. During home walking sessions, adherence to prescribed exercise parameters will be facilitated with the use of personal heart rate monitors with data upload capability. A relatively small number of subjects will be enrolled in this initial ‘proof-of-concept’ project so that feasibility, efficacy, and safety of the research plan may be assessed in a timely and economical manner. Findings will be used in the planning of a clinical trial of exercise and supplemental L-arginine in a large study population.

Won-Kyung Cho, MD
$50,000/yr for 2 years

• Yale University
• Associate Research Scientist
• Internal Medicine

Grant Title: The Role of IL-13 in the Pathogenesis of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension is a lethal disease that is caused by elevated pulmonary vascular resistance. Thus far, the underlying mechanism of PAH has not been clearly understood and there is no cure for PAH. Therefore, a better understanding of the pathogenesis of PAH is desperately needed to improve clinical outcome. Our preliminary studies demonstrated that chronic IL-13 overexpression in murine lungs, led to significant vascular remodeling and features of clinical PAH. We will further explore the mechanism of IL-13-induced pulmonary arterial hypertension in our proposed studies from which we expect to obtain novel insights regarding the pathogenesis of pulmonary hypertension.

Yang Zhou, PhD
$40,000/yr for 2 years

• Yale University
• Postdoc Associate
• Internal Medicine

Grant Title: Chitinase 3-like 1 (CHI3L1) as a Biomarker and Therapeutic Target in the Pulmonary fibrosis of Hermansky-Pudlak Syndrome

Pulmonary fibrosis develops in a subset of patients with Hermansky-Pudlak Syndrome (HPS), and is a major cause of morbidity and mortality. Despite considerable efforts to understand the potential causes for lung involvement in this disorder, there is no biomarker with the ability to predict which patients with the HPS mutations develop pulmonary fibrosis. Moreover, little is known about the mechanisms that drive the progressive fibrotic response in HPS patients and no known effective therapeutics have been described. Chitinase 3-like 1 (CHI3L1) is a prototypic chitinase-like protein produced by a variety of cells. It can be readily detected in the circulation of normal individuals and is greatly up-regulated in the circulation and/or tissues from patients with a variety of diseases characterized by inflammation and/or tissue remodeling. Our studies demonstrated that the levels of CHI3L1 are increased in the circulation of HPS patients compared to normal controls and that the levels are higher in HPS patients with lung fibrosis. Experiments designed in this proposal will combine our extensive experience in understanding the role of CHI3L1 in animal models of HPS and HPS patients to obtain novel and important insights into identifying CHI3L1 as a viable biomarker and a therapeutic target of fibrotic lung disease in HPS.

Kazuyo Kegan, PhD
$50,000/yr for 2 years

• Johns Hopkins University School of Medicine
• Research Associate
• Anasthesiology and Critical Care Medicine

Grant Title: Hypoxia-inducible factor-1 mediates Th2 immune response during development of pulmonary hypertension

Injury to endothelium may be a trigger of pulmonary vascular remodeling in pulmonary hypertension (PH). When the pulmonary endothelium becomes damaged, wound repair cascades are stimulated. Recently, bone marrow-derived cells and circulating immune cells have been suggested to be recruited to the site of remodeling vascular wall, as well as lung resident cells, for this repair process. Failure to stop the initial repair response could result in pathophysiological vascular remodeling. T lymphocytes that express CD4 are also known as T helper (Th) cells; they are regarded as the most prolific producers of cytokines. We have previously shown that Th2 cytokine IL-4 is critical to the initiation of proliferating activity in the pulmonary vasculature and development of PH. In this proposal, we will dissect the mechanism by which the Th2 response triggers endothelial injury and recruitment of bone marrow and immune cells to the site of remodeling vasculature during the development of PH. The purpose of this proposal is to provide a better guide for the therapies that are based on the central role of endothelial injury and circulating cell recruitment caused by innate immune response.

Adebolajo Adeyemo, MB.BS, MSc
$5,000 (1 year)

• University of Ibadan, Nigeria
• Medical Research Fellow/Consultant ENT Surgeon

Grant Title: Biomass combustion and burden of upper airway inflammation

Biomass fuels are unprocessed solid fuels derived from plant or animal material and are burnt to cook or to provide lighting and heating.  More than 700 million homes in Africa depend on biomass fuel for household energy but biomass fuel is not clean energy. It is a major source of indoor air pollution. Long term exposures to biomass smoke have been associated with serious health hazards. The goal of this study is to identify biomarkers of health hazards associated with biomass exposure.

Adaeze Ayuk, MB.BS, Sr. Registrar
$5,000 (1 year)

• University of Ibadan, Nigeria
• Medical Research Fellow/Consultant ENT Surgeon

Grant Title: Spirometric reference values in school-aged children in SE Nigeria

Lung function measurements include spirometry and peak flow measurement. Spirometry is a test that measures how an individual inhales or exhales volumes of air as a function of time. It is a very important method of screening for respiratory problems such as asthma, chronic obstructive pulmonary disease, the same way that blood pressure provides important information about general cardiovascular health. Spirometry is done with the spirometer machine. The child who is eligible to participate will be asked to blow as hard and as fast as he can into the machine and the machine notes how well the lung functions by recording the values of the blows. Measurements will be grouped according to age, height and gender. For each child,the best of 3 blows which are considered good will be used.

Very few research work in spirometric lung function in children, have been done especially in Nigeria. Spirometric lung function values among Africans are known to be different from that in Caucasians and this will affect accurate evaluation of diseases if values from people with different ethnicity are interchanged. This study hopes that by doing spirometry in normal Nigerian children we can find out what the normal values for the different measurements that the spirometer machine measures (FEV, FVC etc). With the knowledge of what the normal values are for Nigerian children, it becomes easier to determine a cut off value with which Nigerian children with abnormal values, that indicate presence of a respiratory problem, can be more accurately detected. This will serve as a reference value. Reference data are important for interpreting pulmonary function test results and can aid in the management of respiratory diseases.This study hopes to help define values that can be used as reference for more accurate interpretation of spirometry in Nigerian Children and therefore assist in other studies that may require normal reference values for children from this region.

Bamidele Adeniyi, MBChB, FWACP
$5,000 (1 year)

• Federal Medical Center, Owo, Ondo State, Nigeria
• Consultant Chest Physician

Grant Title: Pulmonary Function Among Petrol Pump Workers in Owo-Southwestern Nigeria

This study aims at studying pulmonary functions among petrol pump workers in Nigeria.

Nigeria’s economy is mainly driven by the petrol chemical industry. Due to the proposed deregulation of the petroleum sector, there has been a proliferation of the petrol selling stations across the country. These filling stations are manned by unskilled workers who dispense petrol to consumers. It is well known as established by previous studies, that exposure to petrol fumes  can cause deleterious effect on the body systems .These petrol pump workers do not wear protective devices during their work and some work for as long as 12 hours each day. They also do not have pre-employment lung functions done nor periodic evaluation to assess the effect of the exposure to petrol fumes on them. This study thus aims at assessing the pulmonary functions of the workers and comparing it with their age and sex-matched counterparts who are not exposed to petrol fumes. We shall be looking at a hundred each of the exposed and the non-exposed group and their differences will be statistically analyzed to detect the effect of long-term exposure to petrol fumes on the respiratory functions.

It is hoped that this study, apart from highlighting likely delirious effect of petrol fume exposure, will also serve as a baseline for further larger studies in this areas and among other group of workers; from the drilling to the refining of petrol. It will also serve to inform  policy change towards the use of protective devices for petrol pump attendants.

Ozge Yilmaz, MD
$5,000 (1 year)

• Celal Bayer University (Manisa, Turkey)
• Assistant Professor of Pediatrics

Grant Title: Food allergen sensitivity as a prognostic factor for wheezing in children

Common food allergen sensitization (measured by serum specific IgE) may increase the risk of future wheezing episodes (number of episodes) in young children 1-3 years of age. Food allergen sensitization in these children may be associated with impaired pulmonary epithelial integrity, a mechanism associated wheezing episodes during early childhood. Therefore, in this study we will be investigating the difference of clinical severity and lung inflammation and epithelial integrity in wheezy children with and without food allergen sensitivity documented by Fx5 determination.

This study will consecutively recruit children assisted in a Pediatric Allergy and Pulmonology department; and followed up one year; number of wheezing episodes, emergency department visits for wheezing, number of days of systemic steroid use, number of days of bronchodilator will be assessed every 3 months. Serum levels of surfactant protein D and clara cell protein 16 will be measured at the beginning and end of the study to infer about inflammation and pulmonary epithelial integrity.

Anne Holland, PhD
$40,000/yr for 2 years

• La Trobe University Australia
• Clinical Chair in Physiotherapy, Alfred Health Clinical School     
• Physiotherapy

Grant Title: Where does pulmonary rehabilitation fit in the management of pulmonary fibrosis?

People with idiopathic pulmonary fibrosis (IPF) live with distressing breathlessness, reduced exercise capacity and poor quality of life. We have shown that pulmonary rehabilitation, a program of exercise and education, can improve breathing and walking ability. However not everyone with IPF improves to the same extent and previous studies have not told us when is the right time for pulmonary rehabilitation in any individual. In this study we will randomly assign 94 people with IPF to undertake 8 weeks of supervised pulmonary rehabilitation, or not undertake pulmonary rehabilitation. At program completion and 6 months later we will compare exercise capacity, breathlessness and quality of life between groups, and evaluate whether disease severity affects the amount of benefit achieved. Few treatments for IPF are available and calls are growing for treatments that help patients to live better lives with fewer symptoms. Currently pulmonary rehabilitation is not widely available to people with IPF. This study will provide patients and doctors with certainty regarding the role and timing of pulmonary rehabilitation in IPF, ensuring best possible outcomes in quality of life and community functioning.

Jia Guo, MD, MS
$40,000/yrfor 2 years

• University of Rochester
• Research Assistant Professor of Medicine
• Medicine

Grant Title: Fibrocyte differentiation is regulated by Yin Yang 1 in pulmonary fibrosis

Idiopathic pulmonary fibrosis is a serious form of lung scarring which causes shortness of breath, suffering, and sometimes even death.  Sadly, there are few effective medical therapies for this disease.  This proposal will focus on understanding how scar-forming cells called myofibroblasts accumulate in the injured lung and drive the scarring process.  Recent research by several different scientists has identified that myofibroblasts can be derived from cells that normally reside within the lung or from cells that are produced in the bone marrow and then carried in the blood stream and enter the lung.  These circulating, bone marrow derived cells are called fibrocytes.  Our research team has discovered that a protein called Yin Yang 1 (YY1) regulates the activity of genes involved in promoting the scarring process and can regulate the production and accumulation of myofibroblasts in lung scarring.  In this proposal, we will investigate the mechanisms by which YY1 promotes the formation of myofibroblasts from bone marrow derived fibrocytes and how these cells can then promote lung scarring.  The ultimate goal of our research is to develop therapies to interfere with the functions of YY1 as a novel treatment for idiopathic pulmonary fibrosis and other lung scarring diseases.

Dorothy Cheung, MD
$50,000/yr for two years

• Medical College of Wisconsin
• Assistant Professor
• Pediatrics

Grant Title: Role of human neutrophil subsets in post-viral induced asthma

Early life respiratory viral infections markedly increase the risk for developing asthma and allergic disease.  Further, respiratory viral infections also exacerbate asthma.  However, the question of how a viral infection can influence the development of asthma and allergy has not been answered.  Using a mouse model, we have demonstrated that a specific subset of white blood cells is critical in driving the post-viral asthma disease.  It is not known if this subset of white blood cells is present in humans, nor is it known if they are associated with respiratory viral infections.  We will examine if these cells are present in the nasal lavage fluid of human subjects both during and after an upper respiratory viral infection (i.e., a cold).  These studies will offer important insights into the role of these cells during respiratory viral infections and may provide us with the preliminary data to develop new therapies to prevent the development, or to reduce the exacerbation, of post-viral induced asthma.

Ian Lewkowich, PhD
$40,000yr for 2 years

• Cincinnati Children's Hospital Medical Center
• Instructor
• Immunobiology

Grant Title: Mechanisms of steroid resistance in severe asthma

Asthma is a chronic lung disease resulting from an immune response to normally innocuous environmental components. Disease can range in severity from a nuisance in mild cases, to a life threatening condition in more severe cases. While mild asthma responds to steroid therapy, in severe asthmatics, at higher risk of hospitalization or death, steroids fail to control disease. While mechanisms of steroid resistance are unclear, severe asthmatics have increased Th17 T cell responses, and reduced activity of HDACs, a class of proteins that control the ability of protein products to be expressed from their DNA template. We have recently found that mice with reduced HDAC activity due to a genetic mutation, also develop robust Th17 T cell responses and severe, steroid resistant asthma. The proposed studies seek to elucidate the importance of HDAC1 activity, and Th17 cytokine production in promoting steroid resistance in severe asthma. A greater understanding of the mechanisms driving severe asthma will inform novel therapeutics for individuals with difficult-to-treat asthma.

Howard Huang, MD
$40,000yr for 2 years

• Washington University in St. Louis
• Instructor in Medicine
• Internal Medicine

Grant Title: Role of recipient myeloid cells in lung allograft injury and rejection

Lung transplantation has become a widely accepted treatment option for patients with end-stage lung disease. However, access to this life-saving therapy is constrained by a critical shortage of suitable donor lungs. Moreover, long-term survival in lung recipients remains unsatisfactory, mainly due to a high incidence of chronic allograft rejection manifesting as Bronchiolitis Obliterans Syndrome (BOS). Increasingly, select patients with end-stage BOS are undergoing re-transplantation, placing additional strain on an already limited supply of donor lungs. Thus there remains an urgent need for novel therapies to extend lung allograft survival. Early lung graft injury after transplantation has been associated with increased risk for developing BOS. Accordingly, treatments aimed at controlling post-transplant lung inflammation and injury may improve long-term allograft survival. However, the mechanisms linking lung allograft injury, alloimmunity and rejection remain poorly understood. Preliminary data generated by Dr. Huang and colleagues using a mouse lung transplant model suggest that recipient-derived myeloid cells infiltrating newly transplanted lungs play an important role in shaping the alloimmune response, thereby linking early lung allograft injury to rejection. The studies proposed by Dr. Huang are aimed at identifying the essential cellular determinants of lung allograft injury-mediated rejection. Findings from these studies will provide new insight into which recipient inflammatory cell subsets may be targeted to ameliorate early lung graft injury and promote allograft acceptance.

Tomas Carroll, MS, PhD
$40,000/yr for 2 years

• Royal College of Surgeons in Ireland
• Associate Lecturer
• Medicine

Grant Title: The role of alpha-1 antitrypsin deficiency heterozygosity in COPD

Alpha-1 antitrypsin (AAT) is a protein produced by the liver and certain blood cells that protects the lungs against cigarette smoke and bacterial infection. Alpha-1 antitrypsin deficiency (AATD) is a genetic condition where the body does not produce enough AAT. The lack of AAT in the lungs allows harmful enzymes to cause tissue damage and eventually leads to chronic obstructive pulmonary disease (COPD). Globally, COPD is a growing cause of mortality and will become the 3rd biggest killer by 2020 (World Health Organisation). The most common AAT gene variants associated with disease are the S and Z variants and the most severe form of the condition sees individuals with two copies of the Z variant (ZZ individuals) developing lung disease. However, a lack of clarity surrounds MZ and SZ individuals and whether these carrier individuals are also at risk of lung disease. This is a vital clinical and public health question, as there are over 250,000 SZ and 7.7 million MZ individuals in the US. As AAT is also produced by cells of the immune system, this project will investigate whether MZ and SZ individuals are predisposed to lung disease by exploring whether their normal immune function is impaired. Overall, these studies will determine whether intermediate AAT deficiency is associated with an increased risk of emphysema and will outline possible mechanisms behind this predisposition to lung disease. These studies will generate important new information explaining why lung disease occurs in AATD carriers, and may point towards potential new treatments for the disorder.

Nabeel Hamzeh, MD
$40,000/yr for 2 years

• National Jewish Health
• Assistant Professor
• Internal Medicine

Grant Title: The effect of an oral antioxidant, N-Acetyl-L-Cysteine, on inflammatory and oxidative stress markers in the BAL and BAL cells of sarcoidosis patients.

Sarcoidosis is a granulomatous lung disease predominantly affecting the lungs. Reactive oxidative species are produced secondary to oxidative stress and inflammation and can affect key cellular processes. Our group has shown a role for oxidative stress in chronic beryllium disease (CBD) , a granulomatous disease that resembles sarcoidosis, and have also shown that antioxidant therapy reduces inflammation in CBD. Oxidative stress also plays a role in sarcoidosis but the exact mechanism and potential effect of antioxidant therapy on sarcoidosis is unknown. We will be conducting a pilot study investigating the effect of an oral antioxidant, N-Acetyl-L-Cysteine (NAC), on inflammation and oxidative stress in sarcoidosis. We will measure and compare markers of inflammation and oxidative stress in the lungs of sarcoidosis patients before and after treatment with NAC. Our data will shed light on the role of oxidative stress in granulomatous lung disease and also provide data to conduct a larger clinical study investigating the role of NAC as a therapy for sarcoidosis with physiological and radiographic changes as the primary outcome. This will provide us with a potentially new, non-toxic, therapy for sarcoidosis that can be used on its own or to supplement other therapies minimizing their toxicity.

Laertis Iknomou, PhD
$40,000/yr for 2 years

• Boston University School of Medicine
• Assistant Professor
• Medicine

Grant Title: iPS cell modeling of ChILD syndrome caused by TTF1 mutations

A subset of children suffering from interstitial lung diseases (ChILD) carry mutations in Nkx2-1, a gene important for the development and function of the respiratory system. There is currently no treatment beyond supportive care for those with ChILD disorders, due in part to a lack of understanding of the pathogenesis of the disease. This proposal develops a novel system potentially able to model lung disease in vitro, focusing on the least understood ChILD variant arising from Nkx2.1 mutations. Fibroblasts obtained from individuals with ChILD will be converted into pluripotent stem cells using state of the art reprogramming techniques.  These stem cells will be differentiated into lung epithelial cells in an effort to establish the first in vitro model of lung disease using patient-specific/disease-specific stem cells. If successful, this model system may serve as a powerful high throughput drug screening system potentially leading to the discovery of novel therapeutics to alleviate or even reverse the course of ChILD illnesses.

Diego Ize-Ludlow, MD
$25,000 (1 year)

• University of Illinois-Chicago
• Assistant Professor of Clinical Pediatrics    
• Pediatrics

Grant Title: ROHHAD SYNDROME REGISTRY: DATABASE DEVELOPMENT AND GENOMIC INVESTIGATION

ROHHAD is a rare and devastating disease in which children appear “normal” at birth but have sudden weight gain during early childhood. These children lack the normal sensation of a need to breathe, lose normal control of hormones, and have problems maintaining normal body water and temperature levels. In order to better understand affected children, their clinical course, and how to best help them, we will do 3 things:  1) create a safe and secure internet database that is easily accessible so doctors and families all over the world can share their experiences on the care for children with ROHHAD, 2) We will collect DNA samples, creating the largest ROHHAD genetic bank to help search for a cause of ROHHAD, and 3)  We will look for abnormalities in the number of copies of genes as a possible genetic causes of ROHHAD. Together, these 3 steps will allow us to learn about this complex, rare, and devastating disease, give doctors world-wide a chance to collaborate, and ultimately improve treatment and planning options for ROHHAD patients and families.

Ai (Anna) Lam, MD
$40,000/yr for 2 years

• Northwestern University
• Instructor of Medicine
• Medicine

Grant Title: Selective inhibition of Wnt/beta-catenin signaling as novel therapeutic target for pulmonary fibrosis

Pulmonary fibrosis is a progressive disease that leads to respiratory failure and death. Currently there is no effective treatment for pulmonary fibrosis. Emerging evidence suggest that critical pathways  important in normal development, such as the Wnt/b-catenin pathway, may be implicated in fibrogenesis.  Data from our lab indicate that decreasing Wnt/b-catenin signaling globally in the lung is protective from pulmonary fibrosis. The goal of this current research proposal is to establish a therapeutic rationale for transcription-specific inhibitors of Wnt/b-catenin signaling in pulmonary fibrosis. Thus we propose to develop a transgenic mouse in which expression of the inhibitor of b-catenin transcription activity, ICAT, can be induced in specific cells, such as fibroblasts, and to investigate the effects of ICAT in specific cell types in a animal model of pulmonary fibrosis. We also seek to demonstrate the efficacy of a novel compound inhibitor of b-catenin transcription activity in the prevention/treatment of pulmonary fibrosis, using a mice model. The results from this proposal will provide the foundation for an exciting new class of therapeutics for pulmonary fibrosis.

Yan Sanders, MD, MS
$40,000/yr for 2 years

• The University of Alabama at Birmingham
• Assistant Professor
• Medicine

Grant Title: Epigenetic regulation of Caveolin-1 by TGF-beta mediated signal pathway in lung fibroblasts

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with increasing incidence. No single gene mutation has been found to cause the majority of IPF; environmental factors seem to be more important. Epigenetic regulation, including DNA methylation and histone modifications, which occurs in response to environmental stimuli, plays an important role in regulating gene expression. Caveolin-1 is a critical regulator that is down-regulated in IPF.  Our preliminary and others studies have shown Caveolin-1 can be epigenetically regulated. In this study, we will examine the down-stream pathway activated by TGF-beta, which may result in histone modifications and DNA methylation profile changes related to Caveolin-1 down-regulation. We will determine the degree to which changes in the epigenetic profile of Caveolin-1correspond to its mRNA and protein expression. The related histone and DNA methylation enzymatic changes will also be examined. The keys findings will be examined in IPF animal model and confirmed in IPF tissues. Completion of this study will establish epigenetic regulation as one important factor in the pathogenesis of IPF, which may lead to new therapies to reverse this deadly disease.