Awardees and Abstracts
2011 Awardees
Senior Awards
Daniel H. Conrad, Ph.D.Virginia Commonwealth University
Microbiology and Immunology
The Kainic Acid Receptor-ADAM10 Axis in Allergic Asthma
Dr. Conrad recently made the remarkable discovery that a molecule made by the nervous system (glutamate) stimulates immune cells, known as B cells, to produce a particular type of antibody, called IgE. Reducing IgE in the blood improves asthma, and Dr. Conrad will test the importance of the nervous system-B cell pathway in promoting asthma.
Scientific AbstractJames H. Hurley, Ph.D.University of California, Berkeley (Previously at NIDDK)
Molecular Biology
Molecular Mechanism of Long-term Downregulation of the β2-adrenergic Receptor by ARRDC3
Drugs called Beta2 agonists, which relieve asthma by causing airway muscles to relax, become less effective with repeated use because their target receptor is gradually destroyed. Dr. Hurley, an expert in how cells destroy their own proteins, will define the mechanisms by which Beta2 receptors are destroyed in airway cells, and he will characterize the molecules that are involved in order to develop new therapies.
Scientific AbstractNancy P. Keller, Ph.D.University of Wisconsin-Madison
Medical Microbiology and Immunology
Fungal Lipoxygenases: Microbial Instigators of Asthma
Inhaled fungi have traditionally been thought to trigger asthma by causing an allergic reaction that leads to inflammation in the lungs. Dr. Keller, a prominent microbiologist, will test a new hypothesis that suggests that fungi release chemicals that directly stimulate lung inflammation as well as the production of mucus and the constriction of the airway muscles.
Scientific AbstractJohn S. McMurray, Ph.D.University of Texas, M.D. Anderson Cancer Center
Experimental Therapeutics
Stat6 Inhibitors for the Treatment of Asthma
Asthma is promoted by two cytokines, called IL-13 and IL-4, which are proteins that are released by white blood cells and then circulate through the body to regulate the immune response. Although drugs to block the effects of IL-13 or IL-4 in asthma are in development, and one is already in use, Dr. McMurray has found a new approach that may inhibit both IL-13 and IL-4 at once and, based on this knowledge, will conduct a series of experiments to identify new drugs for the treatment of asthma.
Scientific AbstractCurrent treatments for asthma globally suppress the immune system; for example, medications such as steroids have numerous side effects and render patients susceptible to infections. Dr. Powell’s group has been dissecting the specific immune responses leading to asthma. Their work seeks to better understand the precise immunologic responses that cause this disease, and in doing so, they have identified novel and potentially more selective targets for therapy.
Scientific AbstractJeremy W. Thorner, Ph.D.University of California, Berkeley
Molecular and Cell Biology
Sphingolipid Biosynthesis and Chronic Inflammatory Signaling
The envelope that surrounds all cells and separates them form the outside world is called the cell “membrane”; it is composed of different types of greasy molecules, called lipids. Dr. Thorner will study a particular type of lipid in the membrane, the sphingolipids, which when misregulated may be a contributing factor in susceptibility to developing childhood asthma.
Scientific AbstractRoger Y. Tsien, Ph.D.University of California, San Diego
Pharmacology
Active Targeting of Contrast Agents and Drugs to Sites of Protease Activity in Asthma
Dr. Tsien is the recipient of the 2011 American Lung Association/American Asthma Foundation Senior Investigator Award, given to a non-pulmonologist conducting novel and innovative research on asthma.
A large role for proteases, which are enzymes that operate both inside and outside cells, lies in their precise breakdown of proteins, creating products that can instruct the activity of cells and can alter the tissues surrounding cells. Because both of these functions are thought to be important in asthma, Dr. Tsien will examine the activity of proteases in the lungs of mice during an asthma attack, using new methods he has developed for tracking the activity of proteases.
Scientific Abstract Early Excellence Awards
Edwin C. Jesudason, M.D.Children's Hospital Los Angeles and University of Liverpool
Surgery
Developing Electrophysiological Diagnosis and Curative Therapy for Asthma
The rate at which the heart beats is related not only to input from the central nervous system, but also to its own intrinsic system or “pacemaker,” which sends electrical current across the heart at a regular rate. Dr. Jesudason, a pediatric surgeon who studies lung development, will test the hypothesis that the lung, like the heart, has a self-contained pacemaker network that normally regulates airway caliber in a synchronized manner and that in asthma this regulation becomes skewed toward airway closure.
Scientific AbstractCarla V. Rothlin, Ph.D.Yale University
Immunobiology
TAM Tyrosine Kinase Signaling Pathway Prevents Allergic Airway Hyperresponsiveness
“Antigen presenting cells” are specialized white blood cells that drive allergic responses, which can then trigger an asthma attack. In light of recent evidence that the activity of antigen presenting cells can be shut down through specialized proteins on their surface, Dr. Rothlin will test whether this is true in a model of asthma, in which case these proteins on antigen presenting cells could provide a new target for treating the disease.
Scientific AbstractYaping Tu, Ph.D.Creighton University
Pharmacology
Regulator of G Protein Signaling Proteins: Targets for Treatment of Asthma
One of the most important therapies in asthma is the use of “beta agonists,” which open the airway by binding to proteins called “Beta2-receptors,” found on the surface of airway muscle cells, thereby causing the muscles to relax. Yet, other members of this receptor family trigger airway muscle cells to contract, instead of relax, but there is a certain protein that normally blocks the activity of these receptors, preventing the contractions of airway muscles. Dr. Tu previously has found evidence that these protective proteins may be reduced in asthma, thereby allowing airway muscle cells to contract excessively, so he will test the hypothesis that this is a cause of asthma which, if true, could provide a new pathway for the development of therapies.
Scientific AbstractIrina Udalova, Ph.D.University of Oxford
Rheumatology
Can IRF5-expressing Pro-inflammatory Macrophages Control Allergic Inflammation?
Macrophages are white blood cells that are important in inflammation, including the inflammation that is associated with asthma, but recent studies show that there are different types of macrophages, some of which promote inflammation, while others do not. Dr. Udalova identified a molecule inside macrophages called IRF5 that drives macrophages toward inflammation while its absence prevents this, and she will now examine the role of IRF5 in asthma.
Scientific AbstractExtension Awards
K. Christopher Garcia, Ph.D.Stanford University
Molecular and Cellular Physiology
Novel Approaches to Evolving and Engineering the Interleukin-13 Signaling Axis for Asthma Therapy
Dr. Garcia received a 2005 American Asthma Foundation Early Excellence Award to determine the structure of a shared receptor for the IL-4 and IL 13 cytokines, which are proteins released by immune cells and then bind to other immune cells, altering their function; these two cytokines are especially important in promoting asthma. For this Extension Award, Dr. Garcia will alter the structure of IL 13 so that it will still bind to its receptor, but instead of activating the cells to which it binds, it will shut down signaling through the receptor.
Scientific AbstractThrough studies funded by a 2008 American Asthma Foundation Senior Investigator Award, Dr. Ravichandran found that the death of cells that line the airways leads to the suppression of inflammation, and that this suppression is at least in part due to the release of a protein called IL-10. Based on his additional finding that inhaling IL 10 had the benefit of preventing asthma in mice, Dr. Ravichandran will expand his studies to develop the optimal method for using inhaled IL-10 in the treatment of asthma and to determine its capacity to reverse established asthma.
Scientific AbstractDaniel H. Conrad, Ph.D. — 2011 Senior Award
Virginia Commonwealth University
The Kainic Acid Receptor-ADAM10 Axis in Allergic Asthma
This application will examine the potential of a unique pathway in modulating asthma. Our laboratory has discovered that glutamate signaling through the kainic acid receptor (KAR) leads to enhanced ADAM10 activity and as a result leads to increased production of soluble CD23 and IgE production. This finding is critical because it is one of the first to highlight the importance of a neurotransmitter receptor on B cells and that signaling by this receptor may play a role in IgE mediated disease. Importantly, a specific antagonist of the KAR, NS-102, blocks the KAR and may serve as an innovative pharmacological target for asthma treatment. Two aims are proposed. The immune reactivity of KAR knockout mice will be tested with respect to their B cell proliferative capacity and IgE production. Secondly, the mice will be examined in mouse lung inflammation models. NS-102 or related derivatives will be examined with respect to whether KAR antagonism will modulate lung inflammation. In the second aim, we will look at the role of ADAM10 in lung pathology. Our data indicate that the KAR activity is at least partially explained by ADAM10 and that mice which lack ADAM10 in their B cells or wild type that are treated with an ADAM10 inhibitor have greatly reduced pathology especially in an IgE-mast cell dependent model. In this aim, we will determine if the enhanced immunogenicity is due to exosome incorporation of the IgE complexes and test the hypothesis that ADAM10 blockade inhibits inflammation by blocking Th2 activation.
K. Christopher Garcia, Ph.D. — 2011 Extension Award
Stanford University
Novel Approaches to Evolving and Engineering the Interleukin-13 Signaling Axis for Asthma Therapy
New therapeutic approaches and strategies are needed for patients with severe asthma. Asthma is generally thought to be a Th2 cell-associated inflammatory disease, and the Th2-type cytokines Interleukin-4 (IL-4) and IL-13 are both thought to play major roles in driving asthma pathology in patients. In particular, IL-13 acts on a receptor expressed on lung tissue to induce mucous secretion and a hyper-reactive airway state. Given that IL-4 is also an important regulatory cytokine whose antagonism would likely have adverse effects on immune homeostasis, we are focusing on specific disruption of the IL-13 branch of this signaling axis in asthma. In this proposal we take advantage of existing structural and functional data on the complex receptor biology of IL-13 signaling to engineer this cytokine by selecting variants from combinatorial libraries that will possess both receptor-selective and antagonistic properties. We are taking a very direct route to engineering a high affinity IL-13 ‘dominant-negative’ cytokine for potent blockade of IL-13 signaling. Currently, IL-13 activity as a therapeutic is limited by two factors: 1- IL-13 has a relatively low affinity for its signaling receptor IL-13Rα1, and 2- IL-13 is scavenged from the circulation by the very high affinity decoy receptor IL-13Rα2. Informed by the crystal structure of the IL-13 receptor complexes we determined during the term of our prior AAF award, we will take a mechanism and structure-based approach to increase the affinity of IL-13 for IL-13Rα1, and decrease or eliminate IL-13 binding to IL-13Rα2, while at the same time disrupting the interaction with IL-4Rα. We believe that this affinity maturation can be obtained through mutation of only a few amino acids, and that subverting the hijacking effect of IL-13Rα2 is essential for an effective antagonistic cytokine. The methodologies combine combinatorial biology (yeast display), cell signaling (FACS bar-coding and multi-plexed CyTof), and animal studies in collaboration with the AAF core and other labs.
James H. Hurley, Ph.D. — 2011 Senior Award
University of California, Berkeley (Previously at NIDDK)
Molecular Mechanism of Long-term Downregulation of the β2-adrenergic Receptor by ARRDC3
Inhaled agonists of the β2-adrenergic receptor (β2AR) are the primary treatment for asthma symptoms. They are used by millions of patients world-wide. The major therapeutic benefit derives from β2AR signaling the relaxation of airway smooth muscle cells. One limitation to the efficacy of β2 agonist treatment is tachyphylaxis. Tachphylaxis refers to a decrease in responsiveness to a drug with repeated use. This effect is particularly significant with respect to the bronchoprotective effects of long-acting β2-agonists. These effects are believed to be mediated by desensitization and downregulation of the β2AR. The new hypothesis to be tested in this study is that the arrestin-related E3 ligase adaptor ARRDC3 mediates long-term downregulation of the β2AR. This concept will be investigated at the cellular, molecular and structural levels. The aims of the project are (1) to reconstitute the interactions of ARRDC3 with β2AR and the ubiquitin ligase Nedd4 in vitro, (2) to determine the structural basis for these interactions, and (3) to characterize the cellular itinerary of activated β2AR and ARRDC3 in primary airway smooth muscle cells. This is a basic research proposal designed to yield a definitive mechanistic explanation for β2 agonist tachyphylaxis and to set the stage for translational research to ameliorate it.
Edwin C. Jesudason, M.D. — 2011 Early Excellence Award
Children's Hospital Los Angeles and University of Liverpool
Developing Electrophysiological Diagnosis and Curative Therapy for Asthma
Significance: Asthma is a prevalent, often refractory disease: cures could yield major human benefits.
Hypothesis: Asthma is an airway smooth muscle (ASM) dysrhythmia, that like cardiac dysrhythmias has triggers (e.g. allergens in asthma), but which is curable by ASM pacemaker ablation.
Overall aim: To develop electrophysiological diagnosis and curative therapy for asthma
Rationale:
1. Prenatal airways feature rhythmic peristalsis from large airway pacemakers.
2. Postnatal airways continually modulate their caliber: this homeokinesis is abnormal in asthma.
3. Homeokinesis may provide the background for catastrophic shifts to airway closing in acute attacks.
4. Bronchial thermoplasty is a promising therapy delivered to large and medium sized airways for refractory disease (despite asthma being a small airway problem.
5. We postulate prenatal airway pacemakers persist to generate homeokinesis and bronchoconstriction, and thermoplasty renders distal airways quiescent by ablating these.
Specific Aims:
1. To determine normal airway electrophysiology (EP) and thermoplasty’s impact in vivo.
2. To use airway EP to detect and modulate airway contractility in vivo.
Approach: We will characterize the ‘electropulmonogram’ (EPG) in porcine airway in vivo using intraluminal catheters and extraluminal implanted ones, and assess the impact of thermoplasty and relationship to contractility.
Expected results: We expect to define the EPG and identify pacemakers, whose ablation renders distal airway quiescent.
Caveats: It is unlikely airway electrophysiology is unrecordable given surrounding electrically-active ASM and modern catheters’ reduction of extraneous artifact. If pacemakers cannot be identified, we will, like cardiology, ablate circumferentially around chosen airways to isolate ASM proximally and distally and compare EPGs.
Nancy P. Keller, Ph.D. — 2011 Senior Award
University of Wisconsin-Madison
Fungal Lipoxygenases: Microbial Instigators of Asthma
Fungi have always been associated with asthmatic diseases, for example fungi are recognized as the most serious environmental trigger of childhood asthma in New Orleans post-Katrina. However, as of yet, the exact mechanism(s) by which fungi induce asthma is not known. Our laboratory has recently established a major paradigm shift in fungal/plant signaling where fungi and plants have been found to induce, intercept and recognize each other’s oxylipin signaling molecules. We propose here that a similar ‘stealth by mimicry’ is of consequence in asthma development. Arachidonic acid oxylipins, specifically 5-lipoxygenase derived leukotrienes (LTs), are recognized as critical molecular inducers of inflammation, mucus secretion, vasodilation and bronchial constriction associated with asthmatic diseases; indeed current asthma therapies target both 5-lipoxygenases and LT receptors. This LT induced asthma is presumed to be of human origin. We suggest that in addition to – and possibly in lieu of – human sources, fungal LT play a major role in asthma development. The major hypothesis of this proposal is that fungal lipoxygenases and LTs initiate and/or exacerbate inflammatory asthma. Our three specific aims are to:
1. Elucidate the consequence of Aspergillus fumigatus lipoxygenase(s) entry into host immune cells and determine what LTs they produce,
2. Determine the effect of fungal oxylipins on human cells and recapitulate the fungalasthma relationship in a novel microfluidic in-vitro model, and
3. Assess in vivo models to detect the role of fungal oxylipins in asthma.
John S. McMurray, Ph.D. — 2011 Senior Award
University of Texas, M.D. Anderson Cancer Center
Stat6 Inhibitors for the Treatment of Asthma
Asthma patients have elevated levels of the cytokines IL-4 and IL-13 in their airways, which result in mucus production, airway hyperresponsiveness (AHR), eosinophil recruitment, Thelper cell 2 (Th2) activation, resulting in immunoglobulin class switching to IgE, and inflammation. These two cytokines signal through a common receptor, IL-4Rα, which recruits Stat6 leading to asthma phenotype.
Hypotheses and Specific Aims: The overall hypothesis of this research is that blocking the SH2 domain of Stat6 with cell-permeable, phosphatase-stable peptide mimetics will decrease symptoms of asthma. Such compounds are expected to prevent recruitment of Stat6 to IL-4 and IL-13 receptors and therefore inhibit phosphorylation of Tyr641. This will disrupt the formation of Stat6 dimers, translocation to the nucleus, and expression of downstream genes leading to asthma symptoms. The specific aims are as follows:
Aim 1. Develop high affinity phosphopeptides to the SH2 domain of Stat6.
Aim 2. Study the binding of the peptides to Stat6 using biophysical methods such as isothermal calorimetry and X-ray crystallography. This information will help guide inhibitor development.
Aim 3. Test for ability to inhibit Stat6 phosphorylation in cells stimulated with IL-4 or IL-13. High affinity phosphopeptides will be converted to prodrugs. Dose response and time course will be assessed. Selectivity for the SH2 domain of Stat6 versus the other Stats, p85P13K, and Src, and the inhibition of expression of downstream genes will be determined by western blots of cell lysates.
Aim 4. Test for inhibition of asthma phenotype in mouse models.
Jonathan D. Powell, M.D., Ph.D. — 2011 Senior Award
Johns Hopkins University
Defining and Targeting mTORC1 and mTORC2 in the Pathogenesis and Treatment of Asthma
While the role of Th2 cytokines in asthma has been established, it is clear that asthma is a heterogeneous disease involving the complex interplay of both cells of the acquired and innate immune system. In particular, though atopic/allergen-induced asthma appears to be driven by Th2 cells, it has been suggested that steroid–resistant-disease is mediated byTh17 cells. Our laboratory has identified a central role for mTOR in integrating signals leading to CD4+ T cell effector differentiation. We have determined that mTORC1 signaling controls Th1 and Th17 differentiation while mTORC2 signaling selectively controls Th2 differentiation. Most recently we have identified the downstream mTORC2 substrate SGK1 as a novel mediator of Th2 differentiation. The overall hypothesis of this proposal is that mTORC1 and mTORC2 signaling selectively regulate the generation of atopic and steroid resistant asthma and that pharmacologically targeting these pathways will lead to novel therapeutic interventions. To this end we will test the following specific aims: First we propose that mTORC1 deficient T cell mice will be resistant to Th17-mediated disease, and that pharmacologic inhibition of mTORC1 will prevent/treat this form of asthma. Likewise that mTORC2 deficient T cell mice will be resistant to the development of atopic/allergen-mediated disease and that pharmacologic inhibition of mTORC2 will prevent/treat this form of asthma. In the second Aim we seek to demonstrate that SGK1-/- T cell mice will be resistant to the development of atopic asthma and that pharmacologic inhibition of SGK1 represents a novel means of treating this form of the disease.
Kodi S. Ravichandran, Ph.D. — 2011 Extension Award
University of Virginia
Testing Intranasal Administration of IL-10 in Airway Inflammation
Our current work funded by the AAF has identified both a cellular and a molecular target for further exploration. First, our work demonstrates that the airway epithelial cells play a critical role in establishing tolerance versus airway inflammation. Specifically, the normal function of epithelial cells is a critical tolerance versus airway inflammation. Specifically, the normal function of epithelial cells is a critical determinant when allergens such as the house dust mite are first encountered via the nasal route (as likely to occur in humans). Second, we have identified that the cytokine interleukin-10 level is severely reduced in mice with defective epithelial cell function leading to airway inflammation. Although the source of this IL-10 is still being defined, remarkably, intranasal administration of exogenous IL-10 could almost completely ‘rescue’ the airway inflammation induced by the house dust mite allergen, even when epithelial cell function remains impaired. Reduced IL-10 levels in the BAL fluid of human asthmatics have been observed, but therapies using IL-10 to reverse or alleviate the symptoms have not been reported. Phase I trials with systemic administration of IL-10 do not seem to show short-term toxicity and the half-life of IL-10 in tissues (hrs) also seem reasonable. In this AAF extension award, we propose to test the feasibility of using IL-10 as an aerosol (either alone or with corticosteroids) to limit airway inflammation in the context of specific allergens, first in mice and subsequently in humans. Should aerosol administration of IL-10 prove useful in reversing airway inflammation, this may lead to the rapid development of new therapeutics for asthma.
Carla V. Rothlin, Ph.D. — 2011 Early Excellence Award
Yale University
TAM Tyrosine Kinase Signaling Pathway Prevents Allergic Airway Hyperresponsiveness
Antigen presenting cells (APCs) are fundamental in maintaining immune homeostasis - adroitly keeping the critical balance between immune reaction and immune tolerance. The inappropriate activation of APCs has been proposed to be a key factor in the pathogenesis of asthma. Yet, the mechanisms underlying APC hyperactivation remain unknown. We hypothesize that the TAM (Tyro3, Axl and Mer) receptor tyrosine kinase signaling pathway is triggered in APCs to prevent chronic airway inflammation. This proposal seeks to address the function of TAM signaling in mouse models of asthma. Specifically, we propose (1) to determine whether the TAM receptors function as anti-inflammatory agents in vivo and (2) to identify the mechanism of TAM receptor activation in mouse models of asthma. Our studies will constitute the foundation for future efforts centered on investigating the association of deficiencies in this pathway with human chronic inflammatory diseases of the airways and the pharmacological activation of the TAM pathway in the treatment of asthma.
Jeremy W. Thorner, Ph.D. — 2011 Senior Award
University of California, Berkeley
Sphingolipid Biosynthesis and Chronic Inflammatory Signaling
Asthmas are diseases wherein the patients hyper-respond to allergens, resulting in chronic inflammation of the bronchi leading into the lungs. Animal (mainly murine) models suggest that respiratory tract dendritic cells stimulated by particulate pollutants and microbes secrete cytokines that evoke maturation of airway-homing effector T cells and trigger infiltration by macrophages that release NO, provoking bronchial smooth muscle contraction, thereby inducing airway narrowing. Smooth muscle cells can exacerbate bronchial inflammation by themselves secreting various mediators that recruit and activate additional inflammatory cells (including mast cells). Nonetheless, the molecular bases for the hyper-responsiveness of the immune mechanisms involved in induction and regulation of these processes, which underlie asthma disorders, are not well understood. In the case of childhood (early onset) asthma, however, analysis of genome-wide human sequence variation has linked predisposition for this condition to mutations that up-regulate expression of the ORMDL3 gene, presumably increasing ORMDL3 protein. Recently, the yeast (Saccharomyces cerevisiae) orthologs (Orm1 and Orm2) were shown to bind directly to and negatively regulate serine palmitoyltransferase, which catalyzes the first step in sphingolipid biosynthesis. Thus, the hyper-responsiveness underlying childhood asthma may arise from a reduction in the plasma membrane sphingolipid-to-glycerophospholipid ratio. The specific aims of this proposal are, first, to explore whether experimental treatments and conditions that compromise sphingolipid production affect standard read-outs of immune response and, second, to examine whether these same perturbations specifically cause defects in endocytosis and/or down-modulation of TLRs, cytokine receptors, or other classes of cell surface molecules implicated in asthma pathogenesis.
Roger Y. Tsien, Ph.D. — 2011 Senior Award
University of California, San Diego
Active Targeting of Contrast Agents and Drugs to Sites of Protease Activity in Asthma
Dr. Tsien is the recipient of the 2011 American Lung Assosciation/American Asthma Foundation Senior Investigator Award, given to a non-pulmonologist conducting novel and innovative research on asthma.
Many extracellular protease activities play crucial roles in acute asthma and subsequent chronic airway remodeling. However, little is known about precisely where and when different proteases become enzymatically active in intact animal models, let alone patients. Previous techniques to molecularly image protease activities in asthma have been limited to assessing pooled matrix metalloproteinase (MMP) activity by fluorescence dequenching, an imaging modality with limited depth penetration. We propose to apply a new class of probes for protease activity, activatable cell-penetrating peptides (ACPPs) and their macromolecular conjugates, for which we already have varieties responsive to MMPs, elastase, thrombin, and plasminogen activators. We will start by imaging fluorescent ACPPs for MMPs, elastase, and plasminogen activators during both acute asthma and chronic induction of airway remodeling in animal models, correlating against time, type of stimulation, disease intensity, and genetic background including suppression of individual proteases. Noninvasive epifluorescence and fluorescence molecular tomography will be validated by postmortem histology and biochemical quantitation of probe cleavage and retention. New ACPPs with selectivities for mediators such as MMP-12, ADAM33, chymase, and H2O2 will be developed and analogously tested in these models. These studies may help clarify controversies over where and when different proteases exacerbate vs. ameliorate disease. We will also develop ACPPs for nonoptical imaging modalities such as SPECT, PET, and MRI, whose greater depth penetration makes them more suitable for noninvasive molecular imaging in humans. Finally, we will attempt to use ACPPs to target drug-loaded nanoparticles to sites of high protease activity to increase their therapeutic index.
Yaping Tu, Ph.D. — 2011 Early Excellence Award
Creighton University
Regulator of G Protein Signaling Proteins: Targets for Treatment of Asthma
G-protein coupled receptors (GPCRs) are important regulators of multiple cell types involved in asthma, and drugs targeting specific GPCRs are used to treat asthma. Our long-term goal is to determine whether Regulator of G-protein Signaling (RGS) proteins, intracellular modulators of GPCRs, provides new and more effective targets for treatment of asthma. Recently, we found that asthmatics had reduced expression of RGS2, a member of the RGS family that selectively regulates bronchoconstrictor GPCR signaling. RGS2 knockout mice are predisposed to have AHR, the pathophysiologic hallmark of asthma. In addition, interleukin-13 (IL-13), a key mediator of AHR in allergic asthma, induces a selective RGS2 down-regulation and enhanced contraction of airway smooth muscle (ASM). Since excessive ASM contraction is directly responsible for AHR, we hypothesize that RGS2 is a key regulator of ASM contraction and that IL-13-induced RGS2 repression plays a crucial role in the AHR of asthma. We will test this hypothesis by studies that integrate molecular, cellular, tissue, and animal models. Aim 1 will define the RGS2-regulated signaling pathways mediating ASM contraction; Aim 2 will elucidate mechanisms of IL-13-induced RGS2 repression in ASM cells; Aim 3 will determine the pathological importance of RGS2 repression in ASM in a murine model of asthma. Completion of this project will identify specific aberrant signaling pathways and molecules involved in the enhanced ASM contractility and AHR in asthmatic patients, leading to increased understanding of asthma pathogenesis. The aberrant signaling molecules identified may serve as future therapeutic targets and/or biomarkers for controlling the AHR of asthma.
Irina Udalova, Ph.D. — 2011 Early Excellence Award
University of Oxford
Can IRF5-expressing Pro-inflammatory Macrophages Control Allergic Inflammation?
While the contribution of adaptive immunity and Th2 cells in allergic airway inflammation and acute hyper-reactivity has been extensively studied, the role of innate cells has so far received little attention. Emerging data suggest that macrophages play an active role in inducing airway inflammation and contribute to the development of asthma. Macrophages are a heterogeneous population of immune cells, with distinct phenotypic characteristics and specific roles in promoting T cell lineages. However, transcription factors that underlie macrophage subsets remain largely undefined. This proposal builds on our recent discovery of the master regulator of pro-inflammatory macrophage polarization, the transcription factor IRF5, and investigates its functional role in the pathogenesis of allergy and asthma. Our research may lead to the development of new therapeutic strategies comprising the administration of a therapeutically effective amount of IRF5, or an agent that induces the expression of IRF5 in macrophages.