Awardees and Abstracts

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2007 Awardees

Senior Awards

Leonard P. Guarente, Ph.D.
Massachusetts Institute of Technology
Biology
Sirtuins as Novel Regulators of Inflammatory Responses in Asthma

Scientific Abstract

Theodore S. Jardetzky, Ph.D.
Stanford University
Structural Biology
Molecular Biology and Cell Biology Allosteric Modulators of IgE Receptor Interactions

Scientific Abstract

Kun Ping Lu, M.D., Ph.D.
Harvard Medical School
Medicine
Phosphorylation-specific Prolyl Isomerase Pin1 as a Novel Therapeutic Target in Asthma

Scientific Abstract

Roderick MacKinnon, M.D.
Rockefeller University
Molecular Neurobiology and Biophysics
Biochemical and Structural Analysis of BK Channels: Mediators of Smooth Muscle Contractility

Scientific Abstract

Andrew R. Marks, M.D.
Columbia University College of Physicians and Surgeons
Physiology and Cellular Biophysics
Ion Channels as Novel Therapeutic Targets for Asthma

Scientific Abstract

Michael E. Mendelsohn, M.D.
Tufts University School of Medicine (Now at Genentech)
Molecular Cardiology Research Institute
Cyclic GMP-dependent Protein Kinase Regulation of Airway Smooth Muscle in Asthma

Scientific Abstract

Tim R. Mosmann, Ph.D.
University of Rochester Medical Center
Vaccine Biology and Immunology
Role of Amphiregulin in Asthma and Allergy

Scientific Abstract

Krzysztof Palczewski, Ph.D.
Case Western Reserve University
Pharmacology
Crystal Structure of Beta2-Adrenergic Receptor

Scientific Abstract

Mary E. Sunday, M.D., Ph.D.
Duke University Medical Center
Pathology
Neuropeptides, Immunity, and Asthma

Scientific Abstract

Alexander Varshavsky, Ph.D.
California Institute of Technology
Biology
Asthma, Lung Biology and the N-End Rule Pathway, a Sensor of Nitric Oxide, Heme, and Redox

Scientific Abstract

Early Excellence Awards

Colin S. Duckett, Ph.D.
University of Michigan
Pathology
IAP Proteins as Novel Molecular Targets for the Treatment of Asthmatic Disease

Scientific Abstract

Joel N. Hirschhorn, M.D., Ph.D.
Harvard Medical School
Medicine - Genomics
Analysis and Follow-up of Genome-wide Association Studies of Asthma

Scientific Abstract

Sven-Eric Jordt, Ph.D.
Yale University
Pharmacology
Sensory Chemoreceptors in Asthma and Airway Hyperresponsiveness

Scientific Abstract

Susan M. Kaech, Ph.D.
Yale University
Immunobiology
Identifiying the Signals that Keep TH2 Memory CD4 T Cells Alive During Chronic Asthma

Scientific Abstract

Dana J. Philpott, Ph.D.
University of Toronto
Immunology
Dysregulation of Nod Protein Function in the Development of Asthma

Scientific Abstract

L. Keoki Williams, M.D.
Henry Ford Health System
Internal Medicine
Genetic Determinants of Inhaled Steriod Response in African-Americans with Asthma

Scientific Abstract

Extension Award

Danuta Radzioch, Ph.D.
McGill University
Experimental Medicine and Human Genetics
Preclinical Studies on the Application of TLR7 as a Therapeutic Agent Against Allergic Asthma

Scientific Abstract

2007 Awards Project Abstracts

Colin S. Duckett, Ph.D. — 2007 Early Excellence Award

University of Michigan

IAP Proteins as Novel Molecular Targets for the Treatment of Asthmatic Disease

The Inhibitor of Apoptosis (IAP) proteins were originally described as a family of intracellular proteins with key regulatory roles in the suppression of the apoptotic cell death pathway. Recently, however, studies performed by a number of laboratories, including ours, has revealed numerous cellular functions for the IAPs that appear unrelated to apoptosis, and genetically targeted Iap-deficient mice exhibit very few, if any, differences in terms of apoptotic sensitivity. However, using an established model of asthma induced by administration of cockroach antigen, we have found dramatic alterations in the lungs of mice deficient in one member of the family c-IAP1. Consistent with these structural changes, c-IAP1-null mice exhibit a profound alteration in response to respiratory syncytial virus (RSV) challenge, which is known to greatly potentiate the severity of asthmatic disease. We therefore propose to explore the role of the IAPs using genetically targeted mice, as well as a range of IAP antagonists available to our laboratory. Although these antagonists were initially generated through structure-based synthetic design as targeted anti-cancer reagents, our initial findings raise the exciting possibility that by phenocopying IAP-null mice, they might additionally function as a novel class of anti-asthmatic drugs.

Leonard P. Guarente, Ph.D. — 2007 Senior Award

Massachusetts Institute of Technology

Sirtuins as Novel Regulators of Inflammatory Responses in Asthma

Asthma is a disease involving local and systemic allergic inflammation, which leads to airway obstruction and respiratory insufficiency. A positive correlation has been found between asthma (and certain other inflammatory diseases) and obesity (and the related metabolic syndrome). Calorie restriction (CR) triggers physiological changes opposite to metabolic syndrome, and has been shown to extend life span and mitigate many diseases in rodent models. This proposal will test whether asthma can be mitigated by CR, and whether genetic alterations in the SIRT gene family, encoding mammalian sirtuins, impact this disease. In Aim 1, we will test the effects of CR or high fat diets in a mouse asthma model. We will also determine the effects of reducing or increasing the activity of SIRT1 and other sirtuin genes on this disease. If effects are found, we will pinpoint tissues in which SIRT1 or other sirtuins affect asthma by using tissue specific knockout mice and bone marrow transplantation. In Aim 2, the effects of resveratrol and other activators and inhibitors of SIRT1 will be tested in the mouse asthma model. If appropriate, novel inhibitors of other sirtuin proteins will also be identified. These studies will show whether CR mitigates asthma and which SIRT proteins might be involved in these effects. We hope our findings will provide a mechanistic connection between sirtuins and asthma that leads to novel compounds for treating asthma in people.

Joel N. Hirschhorn, M.D., Ph.D. — 2007 Early Excellence Award

Harvard Medical School

Analysis and Follow-up of Genome-wide Association Studies of Asthma

Asthma is a major public health concern. Environmental factors play a prominent role in developing asthma, but about half of the variation in asthma susceptibility is due to inherited factors. Discovery of the genetic contributors to asthma would provide important insights into why patients get asthma, with potential implications for prognosis, diagnosis, treatment and prevention. Despite many reports of association between DNA sequence variants and asthma risk, no genetic variant has been convincingly and consistently associated with asthma in multiple studies, indicating that the genetic factors underlying asthma remain largely undiscovered. Genome-wide association studies, using hundreds of thousands of genetic markers across the genome, offer a new, comprehensive and powerful method for gene discovery. Distinguishing bona fide associations from false leads that can emerge from such large studies is crucial, and requires large sample sizes, rigorous analysis, and replication of results. We will build on our experience in genome-wide association studies to avoid false positive findings, and use novel methods to search for different classes of variants (common and rare) that influence asthma risk.

Specifically, we propose to: Analyze and combine genome-wide association data from multiple population-based cohorts, encompassing nearly 20,000 individuals in whom genotype and asthma-related phenotype data will be available;
Validate preliminary associations in additional cohorts;
Perform follow-on functional and fine-mapping studies of associated variants; and
Utilize a well-phenotyped inner-city cohort to extend findings to underrepresented minority populations and search for interactions between validated genetic associations and other environmental, genetic or clinical risk factors.

Theodore S. Jardetzky, Ph.D. — 2007 Senior Award

Stanford University

Molecular Biology and Cell Biology Allosteric Modulators of IgE Receptor Interactions

Allergic reactions are the predominant cause of asthma and result from the activation of IgE antibody receptors on mast cells. Allergen-specific IgE antibodies bind to a high affinity receptor, FceRI, coating the surface of mast cells, and priming these cells to respond with a powerful inflammatory response. Inhibition of the IgE receptor interaction can decouple the antibody recognition of allergens from the downstream inflammatory response, and therefore provide a potentially comprehensive approach to blocking diverse allergic responses to different environmental agents. The IgE receptor interaction can be inhibited therapeutically by anti-IgE antibodies, but this treatment is expensive and not suitable for all potential patient populations. Additional approaches to inhibiting this step of the allergic cascade may therefore have significant potential therapeutic value. Our structural analyses of the IgE:FceRI complex and the IgE-Fc alone reveal an unanticipated level of flexibility in the receptor-binding domains of the antibody. In the receptor-bound state, we observed the IgE-Fc to be in an open conformation, while in the unliganded crystal structure we observed the IgE-Fc to be in a closed conformation incompatible with receptor binding. We have obtained additional structural and biochemical evidence for this dynamic flexibility in the IgE-Fc and used mutagenesis to trap the IgE-Fc closed conformation. We propose to develop novel assays for monitoring the IgE-Fc dynamics, to study the effects of known IgE ligands on the IgE-Fc conformation, and to identify allosteric modulators of the IgE-Fc, with the goal of developing a novel class of FceRI-binding inhibitors.

Sven-Eric Jordt, Ph.D. — 2007 Early Excellence Award

Yale University

Sensory Chemoreceptors in Asthma and Airway Hyperresponsiveness

The objective of our research is to reveal the contribution of chemosensory neurons and their receptors to the disease mechanism of asthma. The airways are densely innervated by sensory nerves that mediate the sensation of pain, measure lung tension and detect chemical hazards threatening the airways. In many asthma patients the C-fibers, the major chemosensory nerve fibers, become hyperexcitable, leading to constant irritation, inflammation and cough sensitization. Sensory neurons actively contribute to inflammation through the release of pro-inflammatory neuropeptides from airway nerve endings. The mechanism of neural sensitization in asthma is currently unclear. We hypothesize that sensory neural hyperexcitability in asthma is caused by activation and sensitization of TRP ion channels, a class of chemosensory ion channels known to mediate pain and inflammation. Our preliminary studies show that TRPV1 and TRPA1, two chemosensory receptors, are strongly sensitized or activated by chemical mediators highly enriched during asthma. Many asthma patients display heightened sensitivity to capsaicin, an activator of the TRP channel TRPV1. To test our hypothesis we will compare respiratory inflammation and airway responsiveness between wild-type, TRPA1-, and TRPV1- deficient mice before and after sensitization with asthma-inducing agents. These studies will be complemented by an analysis of the morphological changes of airway sensory nerves during inflammatory progression. Finally, we will measure functional changes in sensory neurons gathered from mice after respiratory sensitization. To address these aims, we will use a combination of physiological and immunological techniques, as well as genetic and functional imaging approaches.

Susan M. Kaech, Ph.D. — 2007 Early Excellence Award

Yale University

Identifiying the Signals that Keep TH2 Memory CD4 T Cells Alive During Chronic Asthma

Memory T cells are long-lived and respond rapidly to secondary encounter with cognate antigen. Memory Th2 CD4 T cells are the cellular epicenter of allergy and chronic asthma because these cells orchestrate lung inflammation through the secretion of cytokines, namely IL-4, IL-5, IL-13, that cause airway hyperresponsiveness, eosinophilia, mucus hypersecretion and elevated IgE. Although persistent Th2 responses are the underlying cause of chronic asthma, very little is known about how these allergen-specific Th2 memory CD4 T cells develop in vivo and what signals their survival depends on. Our primary Aim for this proposal is to directly characterize the generation of allergen-specific Th2 CD4 T cells and to identify the survival cytokines that maintain these cells long-term in the lung. Using well-characterized, physiologically-relevant systems of acute and chronic asthma to inhaled antigens, we will track the formation of allergen-specific Th2 memory CD4 T cells on a single-cell level in the lungs and other tissues to (i) calculate their numbers, (ii) characterize their expression of cytokine receptors, (iii) identify critical cytokines that sustain this population over long periods of time and (iv) determine if these cytokines also mediate homeostatic turnover of these memory CD4 T cells. Identifying the cytokines that mediate survival of the allergen-specific memory Th2 CD4 T cells is essential to understand Th2 memory CD4 T cell homeostasis. This knowledge may also give rise to novel therapies that can control the number asthma-inducing memory Th2 CD4 T cells in the lung.

Kun Ping Lu, M.D., Ph.D. — 2007 Senior Award

Harvard Medical School

Phosphorylation-specific Prolyl Isomerase Pin1 as a Novel Therapeutic Target in Asthma

Asthma is a chronic inflammatory disease of the airway induced by overproduction of various cytokines, downstream targets of the transcriptional factors NF-kB and AP-1. We have recently discovered a novel prolyl isomerase, Pin1 that has profound impact on certain phosphorylation signaling by catalyzing specific phosphorylation motifs between two distinct conformations. Significantly, Pin1 is crucial for activation of both NF-kB and AP-1 and production of many proinflammatory cytokines in response to different stimuli. Furthermore, Pin1 is activated in eosinophils from the airway of asthma patients and is critical for survival of activated eosinophils and production of GM-CSF, but its role in asthma has not been clearly established. We propose to use our many unique Pin1 tools to test the hypothesis that Pin1 plays a major role in the development of asthma and is a novel drug target for treating the disease. First, we will use Pin1-deficient mice and primary mast cells in mouse and cell models of allergic asthma to examine the importance of Pin1 for the development of asthma. Next, we will determine the regulation of Pin1 activity during asthma and identify key mediators for the Pin1 action in asthma using functional genomics to elucidate the molecular mechanisms of Pin1 in the pathogenesis of asthma. Finally, we will develop delivery systems for our highly specific nanomolar Pin1 inhibitors and test them in cell and mouse models of asthma. We believe that further development of such Pin1 inhibitors when administered intranasally may represent a novel strategy for treating asthma.

Roderick MacKinnon, M.D. — 2007 Senior Award

Rockefeller University

Biochemical and Structural Analysis of BK Channels: Mediators of Smooth Muscle Contractility

High conductance voltage and calcium activated potassium channels (BK channels) play an important functional role in the control of smooth muscle contractility. The opening of BK channels is controlled by membrane voltage, intracellular calcium, kinase activity, and the direct and indirect action of G-protein subunits. Because of their multiple modes of regulation BK channels hold a central position in the biochemical network that controls membrane voltage. In smooth muscle cells membrane voltage through BK channels is tied directly to the control of intracellular calcium, which in turn influences the contractile state of the muscle. In airway smooth muscle it is known that the action of bronchodilators commonly used to treat asthma, such as beta agonists and phosphodiesterase inhibitors, is suppressed when BK channels are inhibited. In theory direct activation of BK channels by small molecules should cause membrane hyperpolarization, closure of voltage-dependent calcium channels, reduced intracellular calcium, and smooth muscle relaxation. Unfortunately clinically useful BK channel agonists do not exist at the present time. One of the main reasons for the shortage of compounds targeting ion channels in general is that ion channels are difficult to produce at sufficiently high levels to study their biochemical and structural properties. My laboratory has advanced technology in this area to the point where eukaryotic ion channels are now within our reach. The specific aims of this proposal is to express, purify, and determine the atomic structure of a BK channel with the long-term goal of achieving pharmacological control of this potential drug target.

Andrew R. Marks, M.D. — 2007 Senior Award

Columbia University College of Physicians and Surgeons

Ion Channels as Novel Therapeutic Targets for Asthma

A predominant feature of asthma is the inappropriate constriction of airway smooth muscle (ASM). Regulating the growth and contractility of muscle represents an important target for the treatment of asthma. We propose to use our expertise in the cardiovascular field to understand basic mechanisms mediating ASM contractility with the goal of developing novel therapeutic approaches for the treatment of asthma. We are uniquely situated to perform these studies due to the availability of the unique genetically altered mutant mice and our access to several unique compounds capable of targeting the ion channels in smooth muscle cells. Contractility is regulated by a feed-back mechanism whereby the localized, transient increase in cytoplasmic Ca2+ concentration due to activation of sarcoplasmic reticular (SR) ryanodine receptors (RyR) activates plasma membrane BK channels (large conductance voltage- and Ca2+-activated K+ channels). The activation of BK channels causes transient membrane hyperpolarization, inhibition of Ca2+ influx through voltage-dependent Ca2+ channels, closing of RyR channels, and a subsequent decrease in smooth muscle tension. We hypothesize that abnormal regulation of RyR and BK channels may be responsible, in part, for the increased ASM reactivity in asthma. We propose to: (1) determine the role of Ca2+ signaling in the regulation of airway contractility; (2) study the crosstalk between K+ (BK) and Ca2+ channels in ASM; (3) treat the asthma-induced ASM hyperreactivity with RyR and BK-modulatory compounds that we have developed, seeking to restore normal ASM reactivity without the side-effects observed with standard therapies.

Michael E. Mendelsohn, M.D. — 2007 Senior Award

Tufts University School of Medicine (Now at Genentech)

Cyclic GMP-dependent Protein Kinase Regulation of Airway Smooth Muscle in Asthma

The mechanisms regulating altered airway smooth muscle (ASM) cell tone and airway reactivity in asthma remain incompletely understood. For vascular smooth muscle (VSM), the most important endogenous relaxation pathway is the nitric oxide (NO)-guanylate cyclase-cyclic GMP-dependent protein kinase type I (PKGI) pathway in which NO activates guanylate cyclase, increasing cGMP levels and activating PKGI. PKGI in turn targets specific VSM molecules that mediate smooth muscle relaxation. Recent evidence supports that in ASM, like in VSM, activators of guanylyl cyclases cause significant cGMP-mediated relaxant and antiproliferative effects. PKGI is therefore a prime but unexplored candidate molecule to mediate ASM relaxation. In this SPAR proposal, we wish to test the hypothesis that PKGI is a critical mediator of ASM relaxation that normally protects against airway hyperresponsivity via interactions with specific molecular targets, including ASM myosin phosphate and Rho/Rho-kinase, and that dysregulation of PKGI is important in the pathogenesis of bronchial hyperreactivity in asthma. Two state-of-the-art mouse models with disrupted smooth muscle PKG signaling will be used: (SA1) a knock-in mouse harboring a discrete mutation in the protein-protein interaction domain of PKGI, which disrupts NO-PKG-mediated smooth muscle relaxation by disrupting the PKGI-myosin phosphatase complex (leucine zipper mutant or LZM mouse); and (SA2) an inducible, conditional knockout mouse allowing smooth muscle cell-specific deletion of PKG from SMC. Each of these mouse models are currently in the PIs laboratory and will be characterized in vivo and in vitro to explore the mechanism of PKGI-mediated ASM relaxation and the role of PKGI in asthma models. These experiments will provide better understanding of ASM relaxation at the molecular level and have the potential to identify novel gene targets for the development of new therapeutic approaches to bronchoconstriction in asthma.

Tim R. Mosmann, Ph.D. — 2007 Senior Award

University of Rochester Medical Center

Role of Amphiregulin in Asthma and Allergy

Asthma is due to multiple factors, including allergic immune responses, and remodeling of lung structures due to chronic inflammation. The Th2 subset of CD4 T cells, producing IL-4, IL-5 and IL-13, are major inducers of allergic responses, and IL-5 and IL-13 may exacerbate asthma by stimulating eosinophils and fibroblasts, respectively. Amphiregulin and other Epidermal Growth Factor family members have been implicated in mucus secretion and tissue remodeling in asthma. We recently found that activated Th2 cells selectively express amphiregulin, which may further link the allergic and tissue remodeling aspects of asthma. Although Th1 and Th2 are major subsets of mouse and human CD4 T cells, additional diversity exists. Our preliminary evidence suggests stable cytokine pattern heterogeneity within human Th2 cells specific for dust mite allergen. Hypothesis: Amphiregulin derived from Th2 cells contributes to asthma by enhancing mucus secretion and/or tissue remodeling. Inflammation, tissue remodeling and mucus production will be measured in wild-type and Amphiregulin-/- mice immunized to induce acute or chronic airway hypersensitivity. The contribution of T cell-derived amphiregulin will be tested by adoptive transfer of T cells. Hypothesis: Allergen-specific CD4 T cells in asthmatic patients produce more Amphiregulin than non-allergen-specific T cells. Asthmatic; allergic (non-asthmatic); and non-allergic human subjects will be recruited. Cytokine patterns will be compared between T cells specific for allergens versus other recall antigens, using single-cell multicolor Fluorospot and flow cytometry assays. The stability and differentiation requirements of T cells producing amphiregulin will be tested.

Krzysztof Palczewski, Ph.D. — 2007 Senior Award

Case Western Reserve University

Crystal Structure of Beta2-Adrenergic Receptor

G protein-coupled receptors (GPCRs), including ß2-adrenergic receptor (ßAR), are important targets to control asthma episodes, because they play a central role in airway resistance, and many current asthma drugs target these receptors. Thus, GPCR-mediated regulation of Airway Smooth Muscle (ASM) tone and ASM growth is a primary pharmacological target of the acute and chronic features of asthma. Unfortunately, the integral membrane nature of GPCRs has so far precluded their use in structure-based drug design methodologies. The only three-dimensional X-ray crystallographic model for a GPCR is that of rhodopsin. The breakthrough on rhodopsin structure was facilitated in part by its highly enriched and homogeneous expression in the rod photoreceptors of the retina. Such abundant native expression is not available for other GPCRs. As a proof of concept, we used transgenic Xenopus laevis to genetically convert these retina rod cells into bioreactors to successfully produce 30 functionally active GPCRs that were homogeneously glycosylated and were easily purified by immunoaffinity chromatography by taking advantage of a C-terminal tag. We propose to employ a similar mouse expression system, which we are currently utilizing in our laboratory for the production of other GPCRs, for the production of ßAR for structural studies by X-ray crystallography as a prelude for identification of novel, highly specific agonists and antagonists, and allosteric regulators that interact at sites other than the ligand binding site. Hence, this project will be a giant leap forward in providing structural information for this important class of receptors and in more effective treatment of asthma.

Dana J. Philpott, Ph.D. — 2007 Early Excellence Award

University of Toronto

Dysregulation of Nod Protein Function in the Development of Asthma

Asthma likely stems from abnormal cross-talk between the innate and adaptive systems, which may well be initiated at the level of the epithelium. Innate immune signaling, including through the induction of Nod proteins, which are members of a family of innate immune receptors, likely plays a key role in this process. Interestingly, polymorphisms in the human NOD1 gene have been linked to asthma where the defect is thought to affect the relative expression of spliced variants of Nod1. Preliminary findings from our group suggest that these isoforms are unable to sense bacterial products and initiate an inflammatory event. Our hypothesis stems from the idea that Nod1 mutations lead to abnormal responses to commensal bacteria, which thereby impacts on the development of mucosal tolerance. Taken together, our studies will certainly shed light on the role of Nod proteins in the development of asthma and may also open up new avenues for the treatment of this disease through the modulation of Nod function.

Danuta Radzioch, Ph.D. — 2007 Extension Award

McGill University

Preclinical Studies on the Application of TLR7 as a Therapeutic Agent Against Allergic Asthma

The Toll-like receptor (TLR) family plays a crucial role in the regulation of immune responses to various antigens. We have previously demonstrated that a synthetic TLR7/8 ligand, the imidazoquinoline S28463, can prevent the development of airway inflammation following allergen challenge in allergen sensitized mice and rats. This powerful immune response modifier was able to completely inhibit inflammatory cytokine expression in the lungs, prevent induction of IgE, dramatically improve lung physiology and prevent airway remodeling of the allergen sensitized and challenged rats. The proposed studies will assess the effectiveness of this immune response modifier in a primate model of allergic asthma. To demonstrate its protective effect against A. suum antigen-induced allergic asthma, cynomolgus monkeys (Macaca fascilaris) will be treated with S28463 and physiological and molecular consequences will be monitored. We postulate that modulation of the interaction between TLR7/8 and their ligands will allow significant therapeutic effect against both acute and chronic allergic asthma. We anticipate that the results of this study will provide a strong rationale for the introduction of this promising new treatment into clinical trials and eventually clinical practice, as a treatment for patients suffering from allergic asthma.

Mary E. Sunday, M.D., Ph.D. — 2007 Senior Award

Duke University Medical Center

Neuropeptides, Immunity, and Asthma

We propose to investigate the role of pulmonary neuroendocrine cells (PNECs) in the pathogenesis of asthma. Our hypothesis is that the neuropeptide gastrin-releasing peptide (GRP) derived from PNECs mediates lung inflammation and airways remodeling. PNECs occur at highest numbers in the bronchioles, the site of greatest airways resistance. GRP is a potent bronchoconstrictor, PNEC hyperplasia follows systemic immunization, and PNECs degranulate with allergen aerosol challenge. However, GRP has never been implicated directly in asthma. My laboratory identified high GRP levels in premature newborn infants that later developed bronchopulmonary dysplasia (BPD). GRP blockade abrogates lung injury in several animal models of BPD, implicating GRP as a pro-inflammatory mediator of this chronic lung disease. GRP triggers proliferation and/or chemotaxis of mast cells, eosinophils, T cells, and fibroblasts. These observations are relevant to this proposal because BPD patients are ~5-10-fold more likely to develop asthma. We will test our hypothesis as follows: #1: We will evaluate the murine ovalbumin model of allergic airways inflammation ± GRP blockade with a novel agent, 77427. Endpoints include pulmonary function, bronchoalveolar lavage analysis, lung expression microarrays and histopathology. We will also test mice lacking the GRP-related receptors: GRP-R and NMB-R. #2: We will assess a second clinically relevant murine model of respiratory syncytial virus (RSV)-induced airway hyperreactivity and inflammation ± GRP blockade. #3: We will screen urine from children at high risk for developing asthma, testing for GRP and proGRP, focusing on children with allergen-induced asthma, BPD, or RSV bronchiolitis. Ultimately, we hope to use GRP blockade to prevent or arrest the progression of asthma in patients of all age groups.

Alexander Varshavsky, Ph.D. — 2007 Senior Award

California Institute of Technology

Asthma, Lung Biology and the N-End Rule Pathway, a Sensor of Nitric Oxide, Heme, and Redox

The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. The functions of the N-end rule pathway include its roles as a sensor of short peptides, nitric oxide (NO), oxygen, and also a sensor of heme. The pathway’s currently known functions are just the tip of the iceberg, and nothing is known, thus far, about specific functions of the N-end rule pathway in the lung. We shall use new genetic tools to identify the functions of the N-end rule pathway in the lung physiology and its perturbations in asthma, with emphasis on nitric oxide. Hypotheses and Specific Aims: 1) Analyses of the lung physiology and its asthma aspects using cre-lox mouse mutants of ATE1 (R-transferase) that make it possible to delete ATE1 (the arginylation branch of the N-end rule pathway) in specific cell types of the lung. Alternatively, the use of tetO-based ATE1 mutants to overexpress, in doxycycline-controlled settings, the R-transferase enzyme in specific cell types of the lung. 2) Investigations, using tetO-based double mutant mice, which conditionally overexpress both R-transferase and UBR1, a Ub ligase of the N-end rule pathway, thereby increasing the activity of the entire pathway in the mouse. The approaches of Aims 1 and 2 will address specific functions of the N-end rule pathway in the lung under normal and asthma-relevant conditions. 3) Discovery of new physiological N-end rule substrates that are present at least in the lung.

L. Keoki Williams, M.D. — 2007 Early Excellence Award

Henry Ford Health System

Genetic Determinants of Inhaled Steriod Response in African-Americans with Asthma

African-American patients with asthma suffer disproportionately with rates of asthma-related hospitalizations, emergency room visits, and death three to five times those of white patients with asthma. Current national guidelines emphasize the use of inhaled corticosteroids (ICS) for asthma control, and consistent use by individuals with persistent asthma is considered necessary to mitigate existing asthma disparities. However, there is considerable variability in ICS responsiveness, and existing evidence suggests that African-American patients may not benefit similarly from regular ICS use. Recently, there has also been a growing awareness of the differences in medication responsiveness by race-ethnicity and of genetic variations (e.g., single nucleotide polymorphisms) which affect drug response. Unfortunately, asthma pharmacogenomics have not been well studied in African-Americans, who share a disproportionate burden of disease. As part of this application we intend to draw upon our experience and our diverse patient population to assemble a cohort of African American patients with asthma. We will quantify ICS responsiveness in this cohort in a manner which carefully considers exposure (i.e., medication adherence). This proposal takes advantage of recent advances in genotyping and analytic techniques to identify loci associated the discrete trait, ICS responsiveness. First, we will perform a genome wide association analysis which adjusts for racial admixture to minimize confounding by population stratification. Second, we will use admixture mapping to identify genomic regions where a particular ancestry is overrepresented in ICS responders. We will also exploit the benefits of our cohort design to examine genetic associations with quantitative traits related to baseline lung function.

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