2009 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

Anna Blumental-Perry, PhD

Tufts Medical Center
Research: “Cigarette-Smoke-Induced Endoplasmic Reticulum Stress Response in the Pathogenesis of COPD”

Cigarette smoking is the primary risk factor for development of chronic obstructive pulmonary disease (COPD). In the US, more than 45 million people are chronic smokers. Ten to twenty percent of chronic smokers develop COPD, which is the fourth-ranked cause of death in the US. There is currently no cure.

Another complication of smoking is oxidative stress. Cigarette smoke has been shown to interfere with protein folding in the endoplasmic reticulum (ER) and elicit ER stress response (ERSR). ERSR helps cells overcome the consequences of stress or eliminates rogue cells by altering expression of genes involved in anti-oxidant defense, cell cycle, inflammation and apoptosis. The role of ERSR in the protection from smoke-induced oxidative stress or its contribution to the development of COPD is unknown.

Dr. Blumental-Perry and her colleagues demonstrated the induction of ERSR after cigarette smoke exposure and they will test whether ER stress mediates the balance between adaptive and apoptotic responses in COPD. Cell culture and mice models for acute and chronic cigarette smoke exposure will be employed to delineate ERSR effectors important for development of COPD. Their research aims to uncover new therapeutic targets for COPD treatment.

ATS/ARDS Foundation/Sepsis Alliance Partnership Grant in ARDS and Sepsis

• Co-funded by the ATS, the ARDS Foundation and the Sepsis Alliance

Nikolaos A. Maniatis, MD, PhD

National and Kapodistrian University of Athens
Research: “Role of Transcellular Permeability via Endothelial Caveolae in Ventilator-Induced Lung Injury”

Acute Lung Injury (ALI) is a serious complication of conditions such as sepsis, pneumonia and severe burns. Features of ALI include extensive lung inflammation, flooding of airspaces with protein-rich fluid filtered through leaky blood vessels (pulmonary edema) and compromise of the lung’s main function, which is to facilitate the passage of oxygen to the blood. Mechanical respiration is frequently required to support patients with ALI. However, mechanical respiration may worsen the preexisting lung condition, resulting in further deterioration of lung function. It also exerts detrimental effects on remote organs (ventilator-induced lung injury-VILI). In fact, a substantial number of ALI-related deaths have been attributed to this treatment.

The observation that blood vessels in lungs with ALI leak fluid and protein from the blood has directed research efforts towards the mechanisms of vascular permeability in health and disease. The prevailing view is that edema fluid in ALI leaks through loosened contact sites between endothelial cells (EC), the cells that line the blood vessel interior. However, an alternate system of protein and fluid trafficking through EC exists, which utilizes cell membrane vesicles called caveolae. The proposed project focuses on the role of the caveolar transport system in albumin (the most abundant protein in the blood), white blood cell and fluid trafficking as a determinant of pulmonary edema accumulation in VILI.

In the first part of the project, Dr. Maniatis and his colleagues will explore if albumin transport across EC via caveolae is accelerated in VILI and constitutes an important determinant of pulmonary edema. In addition, they will test the effects of cholesterol-lowering drugs (statins), which have been shown to disrupt caveolae, as therapeutic agents in VILI. In the second part of the study, they will intervene in the molecular mechanisms that regulate albumin and fluid uptake via caveolae in EC and specifically on the enzyme Src, a known activator of this process. They will test the notion that Src activation in the setting of mechanical stretch can trigger fluid and protein uptake via endothelial caveolae and contribute to pulmonary edema development. These studies could help scientists and clinicians understand the endothelial processes that take place in response to lung overdistention in mechanical respiration. This could lead to useful treatments for a devastating problem that has no specific therapy at present.

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

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

Jeoung-Sook Shin, PhD

University of California, San Francisco
Research: “Role of Fc Epsilon RI Expression on Dendritic Cells in Asthma”

Asthma is a serious inflammatory lung disease affecting tens of millions of adults and children in the United States. One of the best-known pathologic immune responses in asthma is the production of IgE antibodies against allergens. It has long been thought that the pathologic effects of IgE antibodies are mainly mediated by mast cells due to the exclusive expression of high affinity IgE receptor, FcεRI on mast cells in the lungs. However, it has been found that FcεRI is also expressed on dendritic cells (DCs) in humans. DCs play a crucial role in initiating immune responses to virtually any foreign agents, the functional consequence of which is often dictated by specific receptors for the foreign agents. Very little is currently known about the nature of FcεRI-mediated activation of airway DCs to inhaled allergens and its functional role in asthma. Here Dr. Shin and her colleagues propose (1) to characterize FcεRI-mediated activation of DCs, and (2) to localize FcεRI-expressing DCs in human airways by immunofluorescence microscopy using the bronchial biopsy samples obtained from healthy and asthmatic human subjects. This study could reveal a novel cellular player significantly contributing to the pathogenesis of asthma.

ATS/Coalition for Pulmonary Fibrosis Partnership Grants in Pulmonary Fibrosis

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

Melissa G. Hunter, PhD

The Ohio State University
Research: “MicroRNA Regulation in Idiopathic Pulmonary Fibrosis (IPF)”

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease (ILD) with a mean survival of 3 to 5 years. The underlying cause or genetic factors involved in IPF are unknown. Several investigators have performed microarray studies to compare lung tissue from patients with IPF to lung tissue from those with other interstitial lung diseases and normal lung tissue. Several novel targets and markers for the disease have been found.

While these results are exciting, currently, there is no single gene target or pathway identified for the majority of patients with the disease. Thus, focusing on a single gene or protein targets is unlikely to provide these answers for this complex human lung disease. Due to the wide variety of genetic changes observed in patients with IPF, it is possible that mechanisms involved in gene regulation are important. MicroRNAs (miRNA) are small regulatory RNAs that regulate gene expression through either target mRNA degradation or the prevention of protein translation. Changes in miRNA expression occur in many cancers and their role in inflammation is just emerging.

Preliminary data from Dr. Hunter’s laboratory indicate that the expression of several miRNAs encoded by the miR-17~92 cluster is decreased in the lungs from IPF/ILD patients. They also are finding a similar correlation in murine models of pulmonary fibrosis. Notably, the miR-17~92 cluster targets genes, such as metalloproteinases, collagen, and transforming growth factor, which are highly expressed in IPF/ILD. In this study, Dr. Hunter and her colleagues hypothesize that the loss of expression of miR-17~92 cluster contributes to the pathogenesis of pulmonary fibrosis.

Harikrishna Tanjore, PhD

Vanderbilt University Medical Center
Research: “Contribution of EMT to Pulmonary Fibrosis”

Idiopathic pulmonary fibrosis (IPF) is the most common and most severe of the idiopathic interstitial pneumonias with mortality rate greater than 50 percent within three years of diagnosis. Unfortunately, to date there are no effective therapies despite many attempts to find new treatment options. Hallmarks of the disease are shortness of breath, decreased exercise capacity, scarring in lung tissue, and difficulty with oxygen exchange. Under normal conditions, the epithelial cells that line the airspaces work efficiently to maintain normal lung function and normal gas exchange. In some situations, when the lung is injured and these epithelial cells are damaged, an aberrant wound healing process can occur, leaving a scar rather than resolving back to normal. This process of scarring is referred to as lung fibrosis. Unfortunately, many of the aspects in the pathogenesis of lung fibrosis remain unknown; in fact, in most situations, the cause of lung injury is still unknown. With lung scarring, another population of cells known as fibroblasts infiltrates the area of injury and lays down proteins such as collagen. Many studies implicate these fibroblast cells in the scarring, or fibrosis, but it is unknown from where these cells originate. With this proposal, Dr. Tanjore and his colleagues hypothesize that lung epithelial cells can transition to fibroblasts and contribute to the process of lung fibrosis. In these studies, they will perform experiments using special mouse models that allow them to determine the extent to which epithelial cells can become fibroblasts and also analyze critical pathways involved in this process. This research proposal is designed to help scientists and clinicians to understand more about the pathogenesis of fibrosis and the cells, known as fibroblasts, which are implicated in the pathogenesis of lung fibrosis and identify crucial factors governing the differentiation and origin of these cells.

ATS/Cystic Fibrosis Foundation Partnership Grant in Cystic Fibrosis

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

Theresa A. Laguna, MD, MSCS

University of Minnesota - Twin Cities
Research: “Biomarkers of Lung Injury and Remodeling in Cystic Fibrosis”

Cystic fibrosis (CF) is the most common lethal genetic disease in the Caucasian population. Lung disease is the main cause of morbidity and mortality in CF patients. Lung damage from cystic fibrosis starts very early in childhood and is progressive. Lung damage and subsequent healing can negatively affect how the lung functions. The lung is made of elastin, collagen and cartilage. When the lung is damaged, these components break down into pieces that can be measured in urine, sputum and blood. These products may represent markers of lung damage and healing. Dr. Laguna and her colleagues believe that levels of these markers will be present in CF infants, may increase over time, and may be even higher in patients who are sick with lung symptoms. The goal of the study is to measure the amount of these products in urine, sputum and blood of CF infants during healthy times and also during times of pulmonary illness. Dr. Laguna and her colleagues will then compare these levels with well-studied markers of inflammation that are known to improve with therapy. To accomplish this, they will take samples of urine and blood, and perform a bronchoscopy to get a sputum sample, at age 6 months and again at one year. They will also ask for the same samples during any hospitalization for exacerbation. They will compare levels of these markers over time. These studies will help doctors to better diagnose and treat CF lung disease from an early age.

ATS/Foundation for Sarcoidosis Research Partnership Grant in Sarcoidosis

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

Lobelia Samavati, MD

Wayne State University
Research: “Role of Intracellular NOD- like Receptors in Sarcoidosis”
Partial funding for this grant was provided by a generous grant from the Sarcoidosis Research Institute.

Sarcoidosis is an unpredictable multisystem inflammatory disorder which occurs throughout the world, affecting people of all races and ages. Both environmental and genetic factors appear to play a role in the disease. The human body is constantly exposed to various pathogens like bacterial and viral agents. To defeat these pathogens the body is equipped with cellular sensors, which recognize these pathogens and trigger an immune response. Cytosolic receptors (named NODs) detect bacterial components inside the cells. NOD family members recognize microbial components and upon activation they induce inflammatory pathways against invading pathogens. Dr. Samavati and her colleagues hypothesize that abnormalities in NOD sensors play an important role in the development of sarcoidosis. This study will determine whether the sensors of patients with sarcoidosis respond differently to bacterial products than those of control subjects without sarcoidosis. They will also try to identify variants in the genes for the sensors among sarcoidosis patients and will attempt to relate these variants to disease outcome. Ultimately, this research will help scientists and clinicians to understand the causes of sarcoidosis, identify those who are at most risk for developing the disease and find effective drug therapies.  

ATS/The LAM Foundation Partnership Grant in LAM

• Co-funded by the ATS and The LAM Foundation

Elena Lesma, PhD

Università degli Studi di Milano
Research: “Development of a LAM Model by Using Human TSC2-/- Cells Derived from a Renal Angiomyolipoma. A Pharmacological Evaluation”

LAM is a cystic lung disease that occurs in young women, characterized by the invasion of abnormal smooth muscle cells and cystic degeneration of lung parenchyma, infiltration of the axial lymphatics, and renal tumors [e.g. angiomyolipomas (AML)]. LAM affects between 30 and 40 percent of women with tuberous sclerosis complex (TSC), a syndrome caused by mutations in the TSC1 or TSC2 genes. The TSC complex regulates mTOR. From an AML, Dr. Lesma and her colleagues isolated TSC2-/- a-actin smooth muscle (ASM) cells, which have loss of heterozygosity. TSC2-/- ASM cell proliferation depends on epidermal growth factor (EGF) and incubation with anti-epidermal growth factor receptor (EGFR) antibody leads to cell death. The main objective of this project is to study how pathological cells migrate and metastasize and to design an experimental model for the development of pharmacological strategies. Dr. Lesma and her colleagues’ preliminary data using a mouse model injected with TSC2-/- ASM cells, by intraperitoneal injection or endonasal administration, demonstrated cystic lung degeneration and lymphatic infiltration of the lung similar to that seen in LAM. Using this animal model, they plan to define the migratory ability of the cells and the possible tumor formation, signal transduction involving the mTOR pathway, and in vivo effects of rapamycin and anti-EGFR antibody.

ATS/LAM Treatment Alliance Partnership Grant in LAM

• Co-funded by the ATS and the LAM Treatment Alliance

Caroline A. Heckman, PhD

University of Helsinki, Finland
Research: “Lymphangiogenesis and LAM”

Although lymphangioleiomyomatosis (LAM) is a pulmonary disease, observations indicate that LAM may arise from other parts of the body traveling through the lymphatic system to eventually reach the lungs. While the lymphatic system is important for normal health, it is also involved in pathological conditions such as inflammation and cancer. In many cancers, tumor cells metastasize to other parts of the body by accessing the lymphatic system. To gain access, these cells express growth factors that stimulate the growth of new lymphatic vessels, referred to as lymphangiogenesis. These factors include vascular endothelial growth factors VEGF-C and VEGF-D. Expression of VEGF-C is correlated with metastases and high patient mortality; therefore, much research effort has focused on the development of therapeutic agents that inhibit the lymphangiogenic process. While studies showed that LAM cells express VEGF-C and VEGF-D, experimental evidence that LAM cells may similarly access the lymphatic system is limited. These studies aim to understand the relationship between LAM and the lymphatic system and determine if lymphangiogenic inhibitors offer a viable approach for the treatment of this disease.  

ATS/LUNGevity Foundation Partnership Grants in Lung Cancer

• Co-funded by the ATS and the LUNGevity Foundation

Jessica S. Donington, MD

New York University
Research: “Functional Heterogeneity of Osteopontin Isoforms in Lung Cancer”

Osteopontin (OPN) is a ubiquitous glycol-phosphoprotein with numerous normal and pathologic functions. Evidence suggests a crucial role for OPN in the early development and metastatic potential of non-small cell lung cancer (NSCLC), but the molecular mechanisms of these properties are poorly understood. Furthermore, three distinct splice variants of OPN have been identified in humans, but presence and function of the OPN isoforms have not been previously reported in NSCLC. Dr. Donington and her colleagues believe that the individual OPN isoforms play significantly different roles in determining the invasive/metastatic potential of NSCLC. Their observation that OPNa increases migration, proliferation, anchorage independent growth, and invasion while OPNc inhibits these same properties is fortuitous since the only difference between OPNa and OPNc is the transcription of exon 4, a sequence of 27 amino acids in the amino terminus of OPNa. This region should contain the structure that dictates function relevant to at least some of the demonstrated malignant properties. The specific aims of Dr. Donington’s ongoing work are 1) to identify differences in down-stream gene regulation pathways caused by the over expression of OPNa and OPNc isoforms through the performance of Affymetrix oligonucleotide cDNA micro array analysis of mRNA from the NSCLC cell line forced expression with OPN isoforms and controls, 2) to further explore the functional impact of OPNa and OPNc, through a series of knockout experiments using sh-RNA in both their experimental and wild type NSCLC cell lines with high endogenous OPN expression, 3) in vivo validation of differential malignant properties conferred by OPNa and OPNc isoforms NSCLC in mouse xenograft models of tumor growth and metastasis formation. The structural similarities OPNa and OPNc may make OPN ideal for isoform-specific target treatment strategies in NSCLC.

Alexander S. Krupnick, MD

Washington University in St. Louis
Research:“The Basis for Immunological Therapy of Non-Small Cell Lung Cancer”

Lung cancer is one of the most common malignancies in the Western world and accounts for more cancer deaths than the next four most frequent cancers combined. In the year 2000, the worldwide incidence of non-small-cell lung cancer was close to one million cases. What is most discouraging is the overall 15 percent 5-year survival rate for those diagnosed with lung cancer. Such poor survival is due to the fact that the majority of patients present with advanced disease and few patients survive lung cancer once they develop metastases.

Immune-based therapy for cancer recognizes that cancers harbor mutations in common genes that can be recognized by the immune system as foreign proteins. Immune-based therapy has been successful and is currently used in the clinics for treatment of bladder cancer as well as renal cell carcinoma and melanoma. Treatment of lung cancer using immunotherapy has been mostly unsuccessful when compared to other malignancies. Dr. Krupnick’s goal is to study the mechanisms that lung cancer uses to evade the immune system in order to facilitate clinical trials of immune-based therapy.

ATS/Pulmonary Hypertension AssociationPartnership Grants in Pulmonary Hypertension

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

Lunyin Yu, MD, MS

Massachusetts General Hospital
Research: “Role of NHE1 Gene in Development of Pulmonary Hypertension and Vascular Remodeling”

Chronic low oxygen condition (called hypoxia) induces pulmonary hypertension, a disease with high blood pressure in the lungs, by narrowing the lumen of the lung blood vessels with extra smooth muscle cells (termed as vascular remodeling). The Na+/H+ exchanger (NHE) expressed in many mammalian cell types is a protein localized to the plasma and the mitochondrial inner membrane. The function of NHE is to regulate intracellular pH and cell volume by extruding H+ from cells and taking up Na+ into cells. Many growth factors activate the Na+/H+ exchanger on the cell surface which makes the cell alkalotic and able to multiply. The purpose of this grant is to investigate the role of the Na+/H+ exchanger isoform1 (NHE1) gene in development of pulmonary hypertension and vascular remodeling induced by hypoxia and the mechanism by which NHE1 regulates pulmonary artery smooth muscle cell (PASMC) proliferation that results in pulmonary hypertension and vascular remodeling by using NHE1 null mice. This study will provide evidence that the NHE1 gene is a determinant in development of hypoxic pulmonary hypertension and a novel regulatory pathway for NHE1 in mediating PASMC proliferation. The results from this investigation will also provide new approaches for pulmonary hypertension therapy.

Ari L. Zaiman, MD, PhD

Johns Hopkins University School of Medicine
Research: “Inhibition of TGF Beta Signaling in Endothelial Cells: Role in Pulmonary Hypertension”

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by thickening of the blood vessels going through the lungs, otherwise known as pulmonary vascular remodeling. A subject is determined to have PAH when the pulmonary artery pressure rises above 25 mm Hg. Unfortunately, PAH has limited therapies and ultimately leads to right heart failure and a significant risk of death. Several years ago, the gene that causes the disease in families was identified as bone morphogenetic protein receptor II (BMPRII), a member of the TGF family. Subsequently, several other TGF family members have been implicated in the disease. Despite identifying this key signaling pathway, the mechanism by which it participates in the disease is unknown. Dr. Zaiman and his colleagues propose a novel mechanism in which the balance of TGF signaling is critical to the development of PAH. Specifically, they believe enhanced TGF signaling in endothelial cells causes a cellular change (transition) into another cell type which contributes to the pulmonary vascular remodeling. This research is critical because elucidating the mechanism that causes the progression of the disease can lead to the development of more screening tests and therapeutic interventions. 

Unrestricted Grants:

John F. Alcorn, PhD

University of Pittsburgh
Research: “Mechanisms of TH17 Mediated Allergic Airway Disease”

Asthma is a complex human disease characterized by airway hyper-responsiveness (AHR) and inflammation. Despite numerous studies in mice to elucidate the immunologic mechanism of asthma, sufficient treatment options are limited. Clinically, many asthma patients fail to satisfactorily respond to standard steroid therapy and this type of steroid-resistant asthma has been linked to the presence of neutrophillic inflammation in the lung. Recently, the T lymphocyte subset, TH17 cells were shown to play a role in regulating neutrophilic inflammation in the lung, suggesting a potential role for TH17 cells in steroid-insensitive asthma. Work in Dr. Alcorn and colleagues’ laboratory shows that AHR and inflammation induced by TH17 cells is steroid-resistant and may represent a model for steroid-insensitive asthma. Dr. Alcorn and his colleagues propose that neutrophil recruitment to the lung and subsequent production of inflammatory mediators is required for TH17 driven steroid-insensitive asthma. These experiments will clarify the mechanism by which TH17 induce AHR in vivo. In addition, this application intends to determine which products made by TH17 cells are important in initiating airway disease and whether neutrophil recruitment to the lung is essential for TH17-induced pathogenesis. The mouse model herein presents a novel tool to investigate steroid-insensitive asthma and to test the mechanism by which this disease subset occurs. Taken together, the studies intend to identify novel therapeutic targets for severe and steroid-resistant asthma for which adequate treatment regimens are lacking.

Carolyn J. Baglole, PhD

University of Rochester
Research: “Novel Interaction of the Aryl Hydrocarbon Receptor with RelB in Lung Fibroblasts Reduces COPD”

Chronic obstructive pulmonary disease (COPD) is the fourth-leading cause of death in the US. Despite evidence that cigarette smoke causes COPD, there has been little research examining novel pathways that regulate lung inflammation and cell death responses, two processes that are intertwined in COPD. The objective of this research is to characterize a novel cellular pathway that limits cigarette smoke-induced inflammation and apoptosis in pulmonary cells. Lung fibroblasts are abundant, key structural cells that are capable of creating an inflammatory environment. Fibroblasts also undergo apoptotic cell death upon exposure to respiratory toxicants such as cigarette smoke. Loss of fibroblasts due to cigarette-smoke-induced cell death is linked to the development of COPD in susceptible individuals. Dr. Baglole and her colleagues have shown that a transcription factor called the aryl hydrocarbon receptor prevents cigarette smoke-induced pulmonary inflammation. The goal of this research is to understand the molecular mechanism by which the aryl hydrocarbon receptor prevents cell death and emphysema-like changes in the lung in response to cigarette smoke. This research will provide novel molecular insight into two critical events associated with the development of COPD-inflammation and cell death. Establishing that a single intracellular mediator is capable of attenuating both processes involved in COPD is exciting, and one that has significant translational potential. The results from this research can pave the way for the development of better and more selective treatments for smoke/toxicant-induced pulmonary diseases.

Yang Jin, MD, PhD

2009 Carl Booberg Research Awardee
University of Pittsburgh
Research: “Role of Caveolin-1 in Hyperoxia Induced Acute Lung Injury”

Adult respiratory distress syndrome (ARDS) is a devastating syndrome responsible for significant morbidity and mortality in our intensive care units. The mechanism of ARDS is still poorly understood and therapeutic options remain limited. Hyperoxia-induced lung injury is a well-established model which mimics human ARDS and has been used extensively by investigators to better understand the pathogenesis of ARDS. ARDS is characterized by lung cell death. Caveolae are one of the major structures on the cell surface. Caveolin-1 (cav-1) is its major component. Caveolae and cav-1 are present in almost every lung cell type. Although cav-1 is found to be involved in tumor cell death, little is known regarding the role of cav-1 in normal lung cell death and lung injury. Dr. Jin and her colleagues have obtained preliminary data in cells and in live mice which strongly suggests that cav-1 may play a critical role in lung cell death and lung injury. By investigating the role of cav-1 in acute lung injury, they potentially can discover an underlying mechanism of lung injury and ARDS and identify new targets for future therapies directed against ARDS.

Lynette K. Rogers, PhD

The Research Institute at Nationwide Children's Hospital
Research: “Lipoxin Receptor (ALXR) and Inflammatory Resolution in Lung Growth Arrest and the Development of Bronchopulmonary Dysplasia”

Prematurely born infants account for the majority of neonatal morbidity in the US and often develop complications associated with their prematurity. Bronchopulmonary dysplasia (BPD), one of the most common diseases of prematurity, renders infants unable to oxygenate efficiently and can result in life-long health issues. Inflammation, associated with exposure to elevated oxygen concentrations, is a primary mediator in the development of BPD. Although inflammatory responses are essential for immunity, the immature systems in preterm infants may not be equipped to appropriately “turn-off” or resolve inflammatory processes. These studies will focus on inflammatory resolution mechanisms associated with hyperoxic lung injury. One of the most ubiquitous classes of inflammatory resolution mediators is the lipoxins. Lipoxin A4 (LXA4) inflammatory resolution activities are largely mediated through binding as a high-affinity ligand to the ALX receptor (ALXR). Dr. Rogers and her colleagues’ overall hypothesis is that expression of ALXR is altered and/or the availability of LXA4 is decreased with exposure to hyperoxia resulting in defective inflammatory resolution and prolonged inflammatory responses. Their goal is to use the findings to identify potential pathways for development of new therapies to improve the outcomes in preterm infants.