Awardees and Abstracts

2006 Awardees

Senior Awards

John P. Atkinson, M.D.
Washington University School of Medicine
Rheumatology
A Role for Complement-induced T-Regulatory Cells in Human Asthma
Michael B. Brenner, M.D.
Harvard Medical School
Rheumatology, Immunology and Allergy
New Class of Allergens in Asthma
David W. Christianson, Ph.D.
University of Pennsylvania
Chemistry
Structural and Chemical Biology of Arginase in Asthma
V. Michael Holers, M.D.
University of Colorado at Denver and Health Sciences Center
Medicine and Immunology
Mechanisms of Complement Mediated Inflammation in Asthma
Alexandra L. Joyner, Ph.D.
Sloan-Kettering Institute/HHMI
Developmental Biology
The Role of Sonic Hedgehog Signaling During Airway Remodeling in Asthma
Christopher L. Karp, M.D.
Cincinnati Children's Hospital Medical Center (Now at Gates Foundation)
Pediatrics and Molecular Immunology
The Role of Aeroallergen Mimics of TLR Complex Proteins in Asthma Pathogenesis
James L. Manley, Ph.D.
Columbia University
Biological Sciences
Alternative Splicing of mRNA Precursors: Links to Asthma
Ira Mellman, Ph.D.
Yale University School of Medicine
Cell Biology
Dendritic Cell Biology and Asthma
Eric N. Olson, Ph.D.
University of Texas Southwestern Medical Center
Molecular Biology
Toward Transcriptional Therapies for Asthma
Ralph Weissleder, M.D., Ph.D.
Massachusetts General Hospital
Molecular Imaging
In Vivo Imaging of Cellular and Molecular Mediators in Asthma

Early Excellence Awards

Robinna G. Lorenz, M.D., Ph.D.
University of Alabama at Birmingham
Pathology/Laboratory Medicine
Modulation of Allergic Asthma by Gastric Helicobacter Infection
Boris Reizis, Ph.D.
Columbia University (Now at NYU Medical Center)
Microbiology
Dendritic Cells in the Pathogenesis and Therapy of Chronic Asthma
John B. Wallingford, Ph.D.
University of Texas at Austin
Molecular Cell and Developmental Biology
Molecular Basis of Mucociliary System Development and Maintenance
Ding Xue, Ph.D.
University of Colorado, Boulder
Molecular, Cellular, and Developmental Biology
Molecular Genetic and Pharmacological Studies of the ADAM33 Regulatory Network in C. elegans and Asthma

Extension Awards

Richard A. Bond, Ph.D.
University of Houston
Pharmacological and Pharmaceutical Sciences
Efficacy and Tolerability of Oral Nadolol in the Treatment of Mild Asthma
Danuta Radzioch
McGill University
Experimental Medicine and Human Genetics
Preclinical Studies on the Application of TLR7 as a Therapeutic Agent Against Allergic Asthma

2006 Awards Project Abstracts

John P. Atkinson, M.D. — 2006 Senior Award

Washington University School of Medicine

A Role for Complement-induced T-Regulatory Cells in Human Asthma

Asthma is a syndrome of unknown etiology featuring a Th2 dominant immune-mediated inflammatory response to environmental antigens. The basic immune defects predisposing to asthma are unknown as are the regulatory mechanisms that prevent such responses in non-asthmatics. Regulatory T cells (Tregs) have emerged as a central player in the control of immune responses. We have described a novel means to generate Tregs from naive human peripheral blood CD4+ lymphocytes. It requires the cross-linking of CD3 and the complement regulatory protein CD46. These cells possess properties of Tregs as they are dependent on IL-2, suppress proliferation of naive T cells through soluble IL-10 and granzyme B. They also facilitate dendritic cell maturation through secretion of GM-CSF and CD40L. We propose that such cells home to and reside in the airway, gut and skin. In such locations symbiotic as well dangerous microbes coexist along with numerous potential environmental antigens In Specific Aim 1 we will characterize a human Treg population relative to their ability to modulate Th1, Th2 and B cell responses. In Specific Aim 2 we will compare these Tregs in normal and asthmatic individuals. These studies will define the homing pattern, cytokine profile and surface markers of CD46 generated Tregs. We will ask if CD46 generated Tregs reside in lung tissue and regulate immune cells essential to the development of asthma. Our hypothesis is that an aberrant response and a failure to rectify the error in innate immune sensing lie at the core of asthma pathology.

Richard A. Bond, Ph.D. — 2006 Extension Award

University of Houston

Efficacy and Tolerability of Oral Nadolol in the Treatment of Mild Asthma

Study Objectives: To avoid the potential decrease in FEV1 associated with the commencement of asthma treatment with the beta-adrenoceptor inverse agonist, nadolol, by beginning with a sub-therapeutic dose and using a gradual titration to achieve the target dose. Rationale: Previous studies in an allergen-driven murine model of asthma have shown that the effect of the beta-adrenoceptor inverse agonist, nadolol, on airway hyperresponsiveness (AHR) is dependent upon the duration of treatment. Acute administration of nadolol produces an increase in AHR, while with chronic administration there is a decrease in AHR to methacholine (Callaerts-Vegh et al., PNAS, 2004). These data, along with the analogies of these results to the results obtained with certain 'beta-blockers' in the treatment of congestive heart failure (CHF), led to an FDA-approved Phase IIa pilot study to determine the safety and efficacy of nadolol treatment of mild asthmatics. The results of that trial showed that chronic treatment (9 weeks) with nadolol produced a dose-dependent beneficial effect on the PC20 methacholine in subjects with mild asthma. However, as was the case in the murine studies, and in CHF, acute dosing with nadolol produced a deterioration of some pulmonary function tests. For example, 3 of the 10 subjects completing the initial trial experienced a >12% fall in FEV1 following administration of the first dose of nadolol. This first study used a starting dose of 10 mg. While this fall in FEV1 was asymptomatic in these patients due to the mild status of their asthma (their average FEV1 was >90% predicted), this fall in FEV1 could prevent expanding the therapeutic strategy into patients with moderate or severe asthma. Therefore, this second study is designed to determine whether the initial adverse effects of nadolol can be avoided by beginning at a very low dose (1.25 mg) and slowly increasing the dose (every 2 weeks, rather than weekly as in the first sudy), until either the target dose (160 mg) or a maximal tolerated dose is achieved.

Michael B. Brenner, M.D. — 2006 Senior Award

Harvard Medical School

New Class of Allergens in Asthma

A major paradigm for T cell biology is based on the recognition of peptide antigens presented by MHC class I and class II molecules to activate specific T cells. Similarly, the current dogma indicates that the allergens in allergic asthma are proteins. Yet, recent advances in basic immunology reveal that T cells and Th2 polarized responses may also be mediated by CD1 restricted T cells that recognize lipid antigens. Further, recent evidence points to a key role for CD1 reactive NKT cells in IL-4 and IL-13 driven airway hyperreactivity. Since major allergen sources are rich in lipids, we hypothesize that CD1-presented non-protein antigens may be important in asthma. We will focus on molds and environmental hydrocarbon contaminants such as plasticizers as these sources are implicated in asthma and contain CD1 presented antigens. Thus, we propose to extract and identify lipids from molds that stimulate CD1 restricted T cell responses in asthmatics (Aim 1). Since exogenous lipids in vivo are transported in lipoprotein particles, we will fractionate and assay VLDL derived lipids from asthmatics to identify antigens that may have come from unknown exogenous sources (Aim 2). In addition, we will determine if environmental hydrocarbons like plasticizers elicit enhanced CD1 restricted T cell responses that are relevant in asthma (Aim 3). These studies may open the door to understanding a new class and range of antigen specificities in atopic and/or non atopic asthma that would have far reaching impact and could lead to new therapeutic opportunities.

David W. Christianson, Ph.D. — 2006 Senior Award

University of Pennsylvania

Structural and Chemical Biology of Arginase in Asthma

Arginase is a metalloenzyme that catalyzes the hydrolysis of L-arginine to form L-ornithine and urea. We have determined the X-ray crystal structures of human arginases I and II and we have developed tight-binding inhibitors of these human isoforms. Given our advances with regard to the exploration of arginase function in various human diseases, and given the recent discovery that arginase plays a role in asthma, we propose to focus our study of arginase inhibition on the asthma problem with the support of a SPAR award. We will explore the structure-based design and development of new inhibitors using our recently determined X-ray crystal structures of human arginases I and II to guide our molecular design rationale. Specifically, we aim: (1) to design, synthesize, and assay silanediol and silanetriol amino acids as transition state analogue inhibitors of arginase; (2) to determine X-ray crystal structures of human arginase complexed with silanediol and silanetriol amino acid inhibitors; (3) to evaluate the enhancement of NO-dependent airway smooth muscle relaxation by silanediol, silanetriol, and boronic acid arginase inhibitors in ex vivo organ bath experiments; and (4) to evaluate the potentially beneficial in vivo effects of these arginase inhibitors in suppressing elevated arginase levels detected in animal models of asthma. The best inhibitors identified in this work will represent potential lead candidates in the development of a new family of arginase-targeted drugs for asthma therapy.

V. Michael Holers, M.D. — 2006 Senior Award

University of Colorado at Denver and Health Sciences Center

Mechanisms of Complement Mediated Inflammation in Asthma

The complement system has been proposed to play a major role in the pathogenesis of asthma. This hypothesis is based on the presence of increased complement pro-inflammatory activation fragments and their receptors in patients with asthma as well as protection from the development of asthma with complement blockade in mouse models. There are at least three activation pathways and seven unique receptors whereby complement can promote inflammation in target organs such as the lung; however, blocking individual complement receptors has not led to clinical benefit. We have devised a novel method of dampening the entire complement system by the discovery that one pathway, designated the alternative pathway, is required for all seven downstream pro-inflammatory mechanisms to be engaged, no matter how the system is activated. Importantly, preliminary data have shown that blockade of the alternative pathway with a therapeutic with potential application to humans is highly effective in a murine model of asthma. Additional potential limitations of systemic complement inhibition include infectious risk and the necessity to block serum proteins that are present at high concentrations. Using a novel recombinant complement receptor (CR2)-based target inhibition strategy, these two limitations have been overcome and therapeutics can be directed specifically to sites of complement activation. We propose to further develop and test alternative pathway inhibitors for asthma as well as test the hypothesis that systemically administered, CR2-targeted alternative pathway inhibition of complement can ameliorate asthma.

Alexandra L. Joyner, Ph.D. — 2006 Senior Award

Sloan-Kettering Institute/HHMI

The Role of Sonic Hedgehog Signaling During Airway Remodeling in Asthma

Very little is known about what triggers airway remodeling in asthma, or the molecules that lead to hyperplasia of smooth muscle and fibroblasts. Shh and TGFβ are good candidates for being involved in airway remodeling, since they work together to regulate normal lung development and have been implicated in fibrosis. Furthermore, Shh is an ideal target for therapy since effective small molecule antagonists are available, some of which have been shown to be successful in mouse models of diseases. Using a novel fate mapping approach to study cells responding to Shh and conditional mutants recently developed, we will determine whether Shh signaling through Gli proteins is involved in this process, and whether the TGFβ and Shh pathways intersect or are largely independent in airway remodeling. Hypothesis and Specific Aims: 1. Determine the fate of Shh-responding cell populations in the mouse during normal lung airway development and airway remodeling in asthma, using Genetic Inducible Fate Mapping (GIFM) of Shh-responding cells. Hypothesis: Shh-responding cells contribute to the expansion of smooth muscle, fibroblast and epithelial cells during normal airway development and airway remodeling caused by chronic asthma. 2. Determine whether Shh signaling through the Gli proteins is necessary for lung airway remodeling in asthma, and whether TGFβ acts with Shh to regulate airway remodeling by inducing asthma in Gli1 null mutants and mice carrying conditional mutations in Gli2 and Gli3 in the adult lung mesoderm. Hypothesis: Shhsignaling and TGF are required for airway remodeling caused by asthma.

Christopher L. Karp, M.D. — 2006 Senior Award

Cincinnati Children's Hospital Medical Center (Now at Gates Foundation)

The Role of Aeroallergen Mimics of TLR Complex Proteins in Asthma Pathogenesis

These studies aim at a mechanistic understanding of why specific proteins act as aeroallergens in susceptible hosts. Early exposure to high amounts of ambient lipopolysaccharide (LPS) appears to protect against atopy and allergic asthma. On the other hand, LPS can also exacerbate established asthma. Mouse studies have shown that: (a) airway sensitization with an LPS-free model antigen induces tolerance; (b) sensitization with antigen along with low doses of LPS drives Th2 immune responses and allergic asthma; and (c) sensitization with antigen along with high doses of LPS drives Th1 and/or counter-regulatory responses. Mouse models have also provided mechanistic confirmation of the ability of LPS to exacerbate established asthma. TLR4 is the signaling receptor for LPS. Signaling depends on M.D.-2, the LPS-binding member of the receptor complex. The group II major house dust mite allergens (e.g., Der p 2) are members of a novel group of M.D.-2-related lipid-recognition proteins. M.D.-2 and Der p 2 have high structural similarity. Preliminary data suggest that Der p 2 interacts directly with the TLR4 complex, facilitating LPS signaling. These data suggest that: (a) Der p 2 tends to be a target of adaptive immune responses because Der p 2 has intrinsic adjuvant activity; (b) Der p 2 drives aero-allergic responses under conditions of low LPS exposure by shifting the LPS-response curve into the Th2-inducing range; and (c) Der p 2 promotes asthma exacerbation by facilitating TLR4 signaling in airway cells.

Robinna G. Lorenz, M.D., Ph.D. — 2006 Early Excellence Award

University of Alabama at Birmingham

Modulation of Allergic Asthma by Gastric Helicobacter Infection

Over the past 50 years, the incidence of asthma has been increasing in developed countries. This increased incidence has been attributed to a decrease in infections acquired early in childhood, which may shape subsequent immune responses. Although there have been multiple clinical associations between gastrointestinal infections and decreased asthma incidence, it is difficult to move beyond a simple correlation when studying human patients. We propose to directly test this association and its subsequent disease modifications through the use of our laboratory's well-established murine model of gastric helicobacter colonization and inflammation. Our hypothesis states that both the lung and the stomach are components of the common mucosal immune system, and therefore, gastrointestinal colonization and infection can shape the response of the lung to inhaled allergens. Our preliminary data indicates that pulmonary expression of several key initiators of inflammation, such as TSLP and CXCL15, are altered by gastric helicobacter infection. The following specific aims are proposed: 1) Determine the role of helicobacter-induced helper and regulatory T-cells in modulating a murine model of allergic asthma; 2) Investigate the effects of early mucosal exposure to pathogenic bacteria on subsequent development of allergic asthma; 3) Define the importance of changes in TSLP and CXCL15 in helicobacter modulation of allergic asthma. Our expertise in murine models of gastrointestinal inflammation and mucosal immunity will allow us a unique focus on the mechanisms through which pulmonary inflammation develops to inhaled allergens. These results should stimulate further research into novel therapeutic approaches for allergic asthma.

James L. Manley, Ph.D. — 2006 Senior Award

Columbia University

Alternative Splicing of mRNA Precursors: Links to Asthma

Alternative splicing of mRNA precursors is a common mechanism of gene control in human cells. Furthermore, splicing defects are now known to play a role in a large number of human diseases. Although only a few possible examples of association between asthma and defects in splicing have been described, the possibility that this is the case in asthma merits investigation. Here we propose several lines of study to address this issue, and the following Specific Aims are proposed: 1. We will first systematically study the regulation of alternative splicing of glucocorticoid receptor (GR) pre-mRNA. Alterations in GR splicing result in corticosteroid insensitivity and lead to clinically difficult cases of asthma in affected patients. The proposed experiments are aimed at identifying the mechanism of this regulation, and the RNA sequences and protein factors involved, with the ultimate goal of discovering novel targets for future therapy. 2. We propose a series of experiments designed to rigorously test the possible connection between asthma and alternative splicing of the mRNA encoding a molecular pattern recognition receptor, NOD1, and to explore the details of the mechanism that regulates this alternative splicing event. 3. We propose a large-scale microarray-based study aimed at identifying novel asthma-specific changes in alternative splicing. Newly identified genes will be investigated further to gain a broader understanding of the molecular and physiological basis of asthma and as potential therapeutic targets.

Ira Mellman, Ph.D. — 2006 Senior Award

Yale University School of Medicine

Dendritic Cell Biology and Asthma

Dendritic cells (DCs) are well known to play critical roles in regulating the airway immune response and in the pathogenesis of asthma. However, little is known about how they maintain tolerance to environmental allergens while initiating immunity to invading pathogens, often at the same time. Nor is it clear how DC function is altered in the asthmatic lung, making it difficult to contemplate DC-targeted therapeutic strategies. We propose to apply a range of approaches to characterize the cell biology and function of airway DCs in the normal lung and in murine models of asthma. Using animals bearing genetically-encoded reporters and actuators to probe DC function, three fundamental issues will be addressed. (1) We will examine the distribution and dynamics of myeloid and plasmacytoid DCs in normal and diseased lung using high resolution confocal and multiphoton fluorescence microscopy to determine the distribution and dynamics of distinct DC populations in fixed and living tissue. (2) We will determine how airway DCs interact with allergens and pathogens using imaging and biochemical approaches to reveal mechanisms of capture as well as the abilities of distinct DC populations to induce tolerance or immunity to allergens or microbes. (3) Based on our finding that alterations in cell-cell adhesion (via E-cadherin/β-catenin) triggers a potentially tolerogenic pathway of DC maturation, we will determine if adhesion molecule-dependent signals contribute to tolerance. If so, we will test a pharmacologic approach aimed at augmenting tolerance in an effort to diminish the inflammatory Th2 response characteristic of asthma.

Eric N. Olson, Ph.D. — 2006 Senior Award

University of Texas Southwestern Medical Center

Toward Transcriptional Therapies for Asthma

Asthma is a chronic inflammatory disease of the airways characterized by reversible airway obstruction and inflammation. Inappropriate contraction of airways smooth muscle cells in addition to smooth muscle cell hyperplasia and hypertrophy have been implicated in the development of airway obstruction which accompanies asthma. Recently, exciting progress has been made toward understanding gene regulatory changes associated with asthma. In particular, it has been shown that the proinflammatory state associated with severe stages of asthma is dependent on and controlled by alterations in chromatin structure resulting from a change in the balance between histone acetylation and histone deacetylation. Our laboratory has discovered key roles for histone deacetylases (HDACs) and stress-dependent signaling pathways in the control of muscle hypertrophy and pathological remodeling. Given the involvement of abnormal growth and function of airway smooth muscle cells and HDACs in asthma and inflammatory airway disease, we propose to apply our knowledge and unique genetic tools to dissect the mechanisms involved in the pathogenesis of asthma. These studies have the potential to lead to the development of small molecule therapeutics or novel nonsteroidal anti-inflammatory treatments that mimic the actions of corticosteroids on inflammatory gene regulation to prevent or reverse asthma.

Danuta Radzioch — 2006 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 both innate and adaptive immune responses. Asthma pathology is primarily caused by a dysregulated inflammatory response to innocuous allergens. Our results have clearly demonstrated the powerful anti-inflammatory effects of the TLR7 ligand imidazoquinoline S28463 (TLR7L) in both mice and rats. Therefore, we believe that further preclinical investigations are now required so this promising treatment might be introduced into preclinical trials and eventually into clinical practice. Our proposed studies will characterize the kinetics of the protective effect of TLR7L against allergic asthma in Brown Norway rats and A/J and C57BL/6 mice. Next, we will determine the effect of TLR7L against allergen induced asthma in Rhesus monkeys, by monitoring the physiological and molecular consequences resulting from the treatment. We will also perform complete genomic, proteomic and metabolic analysis of TLR7L-treated animals (mice, rats, monkeys), in order to reveal the exact molecular mechanism of the observed protective effect of TLR7L against allergic asthma. These studies exploring the mechanism of TLR ligand-mediated effects on allergic asthma may also explain how environmental factors impact the adaptive immune system, protecting the host against asthma. Based on the preliminary data generated using this promising compound, it is very likely that modulating the interaction between TLRs and their ligands will have significant therapeutic benefits for asthma patients.

Boris Reizis, Ph.D. — 2006 Early Excellence Award

Columbia University (Now at NYU Medical Center)

Dendritic Cells in the Pathogenesis and Therapy of Chronic Asthma

Asthma is a chronic disease caused by aberrant T cell response to innocuous inhaled antigens. As the primary antigen-presenting cell type in the body, dendritic cells (DC) appear critical for asthma development, and therefore represent potential targets of asthma therapy. However, the precise role of DC in the course of chronic asthma and in the action mode of emerging asthma therapies is poorly understood. We hypothesize that conventional DC and interferon-producing plasmacytoid DC (PDC) play important and specific roles in the normal lung homeostasis and at each step of chronic asthma development. We further propose that immunosuppressive drugs used or developed for asthma therapy, such as cyclosporine and peroxisome proliferator activated receptor gamma (PparĪ³) agonists, might work at least in part by modulating DC functions. To address these hypotheses, we are developing genetic approaches for constitutive, long-term cell ablation and gene targeting in DC and/or PDC in vivo. We will now use DC-specific gene targeting to dissect the role of DC in chronic asthma and in anti-asthma therapies, including: (i) the function of DC subsets in the maintenance of tolerance in normal lung and at different stages of chronic asthma; (ii) the role of Pparg in the control of lung DC activation and in asthma therapy with Pparg agonists; (iii) the role of calcium/calcineurin signaling in DC in the development of chronic asthma and its treatment with cyclosporine. Altogether, these studies might elucidate important mechanisms of asthma pathogenesis, and facilitate the development of more selective immunosuppressive therapies for the disease.

John B. Wallingford, Ph.D. — 2006 Early Excellence Award

University of Texas at Austin

Molecular Basis of Mucociliary System Development and Maintenance

Defects in mucus clearance from the airway contribute significantly to mortality in patients with asthma. The mucociliary system, consisting of mucus-secreting goblet cells and ciliated cells, normally generates a constantly overturning layer of protective mucus that lines the airway epithelium. In asthmatic airways, goblet cell hyperplasia leads to an excess of secreted mucus, while a coincident decrease in the number of ciliated cells leads to a deficit in mucus clearance. Moreover, the normally motile cilia atop ciliated airway cells fail to beat effectively in asthmatics, exacerbating defects in tracheobronchial clearance. The molecular mechanisms underlying these defects remain very poorly understood. Here, we propose first to use a very simple model ciliated epithelium to develop specific hypotheses concerning the molecular mechanisms of differentiation in the mucociliary system. We then propose to use mouse models to ask how this knowledge may be used to revert or prevent the mucociliary system defects associated with asthma. Specific Aims include: 1. Determine the role of the Wnt/PCP signal transduction cascade in cilia morphogenesis and function in a model ciliated epithelium. 2. Using data from a pilot screen, determine the molecular mechanisms by which Hedgehog signaling controls ciliated versus goblet cell fate choices in a model ciliated epithelium. 3. Extend findings from Aims 1 and 2 to the mammalian airway epithelium. 4. Test potentially therapeutic manipulations in mouse models for asthma. The data from these experiments will provide a major step forward in understanding and potentially combating deadly defects in the mucociliary systems of asthmatics.

Ralph Weissleder, M.D., Ph.D. — 2006 Senior Award

Massachusetts General Hospital

In Vivo Imaging of Cellular and Molecular Mediators in Asthma

Novel molecular imaging techniques have had a significant impact on the understanding and clinical management of cancer and cardiovascular diseases but have not been used to their full extent to further our understanding of asthma. In addition, immune cells and cellular mediators often behave differently in intact in vivo microenvironments than in in vitro assays. The overall goal of this proposal is to develop and validate novel imaging approaches to identify key molecular and cellular events in experimental airway inflammation and asthma. The discovery effort will utilize a number of agents and approaches pioneered in our laboratory, including amplifiable "smart" enzyme sensing probes, novel cell trackers based on fluorescent nanomaterials, fiber optical detection technology, optical tomography and nuclear imaging techniques. In the first aim we will utilize recently developed protease specific probes to assess pulmonary tryptase, MMP and cathepsin activity during disease progression and its modulation after therapeutic intervention. In the second aim we will use recently developed multimodal (detectable by different techniques), metabolically inert, cell-tagging reagents for serial imaging to assess the mechanisms employed by both anti-allergic Treg cells and CpG motifs to prevent deleterious Th2 responses. We will obtain a signature pattern that has not been perturbed by invasive protocols, and therefore closely represents the unfolding molecular and cellular activities in the effector organ and other sites such as the draining lymph nodes and spleen. The novel imaging techniques will allow us to uncover events in asthma in vivo, ultimately allowing for clinical translation.

Ding Xue, Ph.D. — 2006 Early Excellence Award

University of Colorado, Boulder

Molecular Genetic and Pharmacological Studies of the ADAM33 Regulatory Network in C. elegans and Asthma

ADAM33 is the first asthma susceptibility gene cloned by the positional cloning method and has been implicated in regulating airway remodeling and the functions of lung cells. As a metalloprotease with several distinct protein-protein interaction motifs, how ADAM33 acts as a protease to affect the activities of other membrane proteins and how it interacts with other membrane and extracellular proteins to regulate airway cell interaction, adhesion, and migration become a fundamental issue and are critical for the understanding of ADAM33's involvement in the pathogenesis of asthma and bronchial hyperresponsiveness. We propose to conduct molecular genetic and biochemical studies in C. elegans to identify substrates, regulators, and interaction partners of two C. elegans ADAM33 homologues. In addition, we will apply a newly developed drug screen protocol in C. elegans to search for compounds that can modulate the activity of the ADAM33 regulatory network in combination with using mice asthma models. These systematic genetic, biochemical, and pharmacological studies not only will advance our understanding of the basic biology of ADAM33 but also will reveal the complex network regulated by ADAM33 to promote proper airway remodeling. These studies will lead to identification of new compounds or targets for therapeutic interventions in the treatments of asthma and bronchial hyperresponsiveness.