Awardees and Abstracts

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2010 Awardees

Senior Awards

Daniel J. Dumont , Ph.D.
Sunnybrook Research Institute
Molecular and Cellular Biology
Manipulating the Angiopoietin Signaling Axis to Treat Asthma

Angiopoietins are natural proteins that promote the formation and growth of new blood vessels. Injection or inhalation of one of the angiopoietins, angiopoietin1, suppresses asthma in mice. Dr. Dumont has developed a synthetic peptide (small protein) that mimics the effects of angiopoietin1, but is more stable and more readily delivered as a therapy. He will now study the effects of this peptide on asthma in mice, define how it works, and refine methods for delivering the peptide as a drug. If the peptide is effective, completion of these studies could lead to further testing and clinical trials. Scientific Abstract

Evan E. Eichler , Ph.D.
University of Washington
Genome Sciences
Comprehensive Analysis of the Effects of Copy Number Variation on Asthma

Dr. Eichler proposes to bring an important advance in genetics to the study of asthma. He will go beyond comparison of gene sequences between asthmatics and nonasthmatics by testing the hypothesis that asthmatics have more (or fewer) copies of important genes than do nonasthmatics. This approach has been shown to be important in the genetics of several other inflammatory diseases. Scientific Abstract

Stuart B. Hooper , Ph.D.
Monash University
Monash Institute for Medical Research
Imaging Lung Motion for Studying the Dynamics of Asthma and Its Treatments

In order to better understand asthma, scientists need to be able to examine what is happening in the lung during an asthmatic attack. It is difficult to capture detailed images of the lung, particularly during a breath because breathing-related movement of the lung causes image blurring. As a result, breathing must normally be halted briefly to acquire an image of the lung while it is stationary. Prof. Hooper and his collaborators have developed methods for looking at the lung with greatly enhanced resolution, allowing many images to be captured during a single breath. This approach not only overcomes the problem of lung motion, but also uses lung motion as one important measure of how different regions of the lung function during breathing. He will apply these techniques to the study of asthma in mice and, in particular, to assess how the lung’s movement is altered by asthma and in response to known therapies. Scientific Abstract

Richard M. Maizels , Ph.D.
University of Edinburgh
Institute of Immunology and Infection Research
Suppression of Airway Allergy by Products of Helminth Parasites

Dr. Maizels has shown that allergic responses in mice can be suppressed by a parasitic worm, and he has begun to dissect the mechanisms of this suppression. As part of this work, he has isolated a group of proteins that are produced by the worm and that mimic the effect of the whole worm on immune suppression. He will now take two paths to defining new therapies for asthma. First, he will define the mechanisms by which asthma is suppressed by the worm proteins as a group. Second he will identify the individual worm proteins that mediate the suppression of asthma, seeking new therapeutic agents for asthma treatment. Scientific Abstract

Andrew N. McKenzie , Ph.D.
Medical Research Council
Laboratory of Molecular Biology
The Role of Nuocytes in the Regulation of Asthma

Dr. McKenzie examines the mechanisms by which the immune system attacks parasites. Through his work he has defined a new cell in the immune system (the “nuocyte”) that may be important in asthma. Specifically, the nuocyte is an immune cell that responds to worm infection by producing a protein, called IL 13, which is known to promote asthma. Dr. McKenzie will test the hypothesis that nuocytes may be important in the asthmatic immune response. He will also define how nuocytes develop in asthma, so that they may be eliminated as a means of preventing or treating asthma. Scientific Abstract

Kevin J. Tracey , M.D.
Feinstein Institute for Medical Research
Laboratory of Biomedical Science
Targeting Nicotinic Acetylcholine α7 Receptors in Allergic Lung Inflammation

Dr. Tracey has previously demonstrated that immunity and inflammation are regulated in part by the nervous system. He will apply lessons from this work to the study of asthma. He has identified a protein (receptor) on the surface of blood cells that suppresses inflammation when it binds to chemicals released by nerves. Additionally, he has developed an artificial chemical compound that mimics the effect of the neurologic signals, thereby suppressing inflammation independently of the nervous system. Dr. Tracey will directly test the effect of this compound on asthma. Additionally, he will pursue other avenues to establish the importance of this connection between nerves and inflammation as a possible path for future new ways of treating asthma. Scientific Abstract

Dario A. Vignali , Ph.D.
St. Jude Children's Research Hospital (Now at University of Pittsburgh)
Immunology
Interleukin-35, iTr35 and Allergic Asthma

Cytokines are proteins that are released by cells and serve as “messengers” that cause other cells to turn on, turn off or otherwise change their behavior. Cytokines allow cells to talk to each other at a distance during an infection or an allergic response. Dr. Vignali has discovered a new cytokine, called IL-35, which dampens the immune response that characterizes asthma. Dr. Vignali will test the importance of IL-35 in the normal regulation of asthma and the use of IL-35 in treating asthma. Scientific Abstract

H. Eric Xu , Ph.D.
Van Andel Research Institute
Structural Sciences
Molecular Mechanism of Dissociated Glucocorticoids

Steroids are a mainstay in the treatment of asthma. However, steroids are often accompanied by side effects that can include bone loss, bone fracture, diabetes, and cataracts. Even though inhalation of steroids lessens their side effects, the side effects nonetheless exist. Dr. Xu is trying to make it possible to use steroids for the treatment of asthma and other diseases without their side effects. At the molecular level, there is considerable evidence that the beneficial effects of steroids can be separated from their detrimental effects, but this has not yet been successfully translated into therapies that separate these activities. Dr. Xu proposes to define the structural requirements for the beneficial vs. harmful effects of steroids and for creating new steroid-like molecules that will promote benefit while minimizing harm. Success in this venture would be of great help to the treatment of asthma and many other inflammatory diseases. Scientific Abstract

Early Excellence Awards

Brian A. Cobb, Ph.D.
Case Western Reserve University
Pathology
Commensal Antigen-induced T Regulatory Cells in Airway Tolerance

Dr. Cobb’s proposal builds on the “hygiene hypothesis,” in which exposure to bacteria early in life protects against asthma. His prior research provides evidence that a specific bacterium, Bacteroides fragilis, which is frequent among gut bacteria, may lead to immune suppression. Dr. Cobb will test the hypothesis that a carbohydrate produced by B. fragilis activates “T regulatory cells,” which are cells that suppress immunity. These studies may open the path to a specific means of suppressing asthma by a bacterium that is otherwise thought to live in the gut without adversely affecting humans. Scientific Abstract

Andre Levchenko , Ph.D.
Johns Hopkins University (Now at Yale University)
Biomedical Engineering
Integrative Biology-based Investigation of Interplay between Inflammatory Signaling and Single-cell Mechanics of Human ASM

Dr. Levchenko proposes to use new technologies to study how asthma alters the function of muscle cells that close the airways. Contraction of these muscles is regulated both by proteins that are produced during inflammation (cytokines) and by tissue proteins and non-muscle cells that are normally in direct contact with the muscles. To examine all of these factors together, Dr. Levchenko will use nanotechnology, growing airway muscle cells on tiny surfaces that mimic the normal lung, thus creating a system in which he can measure both the contraction of the muscle cells and their ability to change shape. If successful, these studies may reveal new pathways in the regulation of asthma attacks and the techniques will also greatly facilitate other investigations of human asthma. Scientific Abstract

Carla M.P. Ribeiro , Ph.D.
University of North Carolina, Chapel Hill
Medicine
IRE1β-dependent Airway Mucin Production and ATP Release: A New Pathway in Asthma

The primary cause of death in asthma is the excessive production of mucus (“mucin”), which fills the airways, in effect causing drowning. Dr. Ribeiro proposes to define a pathway by which asthma causes increased production of mucin in the airways. She has previously identified an enzyme, called IRE1-beta, which is selectively expressed in the mucin-producing cells of the airways and intestine. She has further shown that expression of this enzyme correlates with the production of mucin. Dr. Ribeiro will examine the molecular pathways by which IRE1-beta may stimulate the production of mucin in asthma, thus establishing new potential targets for therapy. Scientific Abstract

Thaddeus S. Stappenbeck , M.D., Ph.D.
Washington University, St. Louis
Pathology and Immunology
Role of Microbial Driven Autophagy within Respiratory Airways in the Pathology of Asthma

Although it was once thought that the airways are sterile, recent studies suggest that this is not so; bacteria are found in the airways of normal lungs and are increased in the presence of inflammation. Dr. Stappenbeck, who has previously studied the role of beneficial bacteria on the cells that line the intestine, proposes that certain bacteria help to maintain the normal function of the cells that line the airways, regulating the production of mucin. He will test the role of specific bacteria on the production of mucus by airway cells. He will also use bacteria as probes to alter the activity of airway cells, searching for new molecular targets for asthma therapy. Scientific Abstract

Extension Award

Sven-Eric Jordt, Ph.D.
Yale University (Now at Duke University)
Pharmacology
Sensory Chemoreceptors in Asthma and Airway Hyperresponsiveness

Through his Early Excellence Award, Dr. Jordt made the remarkable discovery that asthma in mice is dependent on a subset of “sensory” nerves that can detect certain chemicals. More specifically, he showed that asthma does not develop if mice cells lack a specific surface protein on nerves, called TRPA1. TRPA1 is involved in sensing chemicals, including ozone and chlorine, and it responds by allowing ions such as calcium to enter nerve cells. TRPA1 plays a role in cough and sneezing, but its role in asthma had not previously been demonstrated. Dr. Jordt additionally showed that by blocking the function of TRPA1 with a chemical inhibitor he could inhibit asthma in mice. He will use his Extension Award to further test this inhibitor of TRPA1 in mice, as well as to test potentially more powerful inhibitors. Scientific Abstract

2010 Awards Project Abstracts

Brian A. Cobb, Ph.D. — 2010 Early Excellence Award

Case Western Reserve University

Commensal Antigen-induced T Regulatory Cells in Airway Tolerance

Chronic airway hyperresponsiveness and chronic inflammation are hallmarks of asthma. While Th2 cells and a number of innate immune cells are generally responsible for the induction of asthmatic airway inflammation, the production of IL-10 by T regulatory (Treg) cells is thought to play a role in blocking inflammation. Epidemiologic studies have shown that immunologic events early in life can have a strong impact on the development of asthma, where early exposure to commensal bacteria is linked to protective regulatory pathways that reduce the risk of developing asthma later in life. These observations provide a link between exposure to commensal bacteria and the induction of IL-10+ Treg cells that can maintain airway homeostasis. Carbohydrate antigens expressed by some commensal bacteria have been shown to down-regulate inflammation in murine models of inflammatory bowel disease. These T cell-dependent antigens also induce human Treg cells in vitro, characterized by suppressive activity against local inflammation via IL-10 secretion. Since exposure to commensal antigens is a beneficial factor in asthma, these observations fit well into the "hygiene hypothesis" whereby exposure to these antigens could provide a protective immune response (Tregs) that reduces the risk of asthma. This proposal therefore seeks to explore the Treg population as a function of exposure to commensal bacteria and how these cells may ameliorate airway inflammation in a murine model of asthma. If successful, these studies could shed light upon the commensal antigens that contribute to airway homeostasis and how they protect against asthma-associated inflammation.

Daniel J. Dumont , Ph.D. — 2010 Senior Award

Sunnybrook Research Institute

Manipulating the Angiopoietin Signaling Axis to Treat Asthma

Asthma is an inflammatory disease of the airways that can lead to vascular remodeling and ultimately decreased lung function. The exact underlying cause of this response remains unclear; however, the development of animal models that recapitulate several of the key attributes of asthma provides a fertile platform from which to uncover new therapeutics. One class of growth factors, the Angiopoietins, are known to affect both the endothelial and inflammatory response to allergens. We (Drs. Dan Dumont and Paul Van Slyke) have developed a completely synthetic Angiopoietin-ligand mimetic, called Vasculotide, and have shown that it recapitulates the cellular signaling properties of Angiopoietin 1. Based on the findings that Angiopoietin 1 is known to protect animals from airway inflammation and hyperreactivity in asthma, we propose to test the following hypothesis: “Vasculotide, a fully synthetic Angiopoietin-1 ligand mimetic, will ameliorate experimentally induced asthma.” If these proof-of-principle studies show efficacy, they will provide a platform from which to further develop Vasculotide as a therapeutic for asthma.

Evan E. Eichler , Ph.D. — 2010 Senior Award

University of Washington

Comprehensive Analysis of the Effects of Copy Number Variation on Asthma

Asthma has a strong genetic component. Genome-wide association studies of asthma with hundreds of thousands of common single nucleotide polymorphisms (SNPs) have revealed some asthma-susceptibility variants. However, these loci explain very little of the genetic risk of developing this disease, suggesting that other types of genetic variation and/or other models of disease may play a role. Copy-number variants (CNVs) are large insertions, duplications, or deletions of DNA sequence. Interestingly, several lines of evidence suggest that CNVs could be important in the development of asthma. First, many associations between common CNVs and disease have been with immune-related phenotypes, such as lupus, Crohn’s disease, and psoriasis. Furthermore, immune genes are over represented in CNV regions. Given the unexplained genetic risk for asthma and the data implicating CNVs in immune-related phenotypes, we hypothesize that common CNVs are an important source of genetic risk for asthma. The broad objectives of this proposal are to perform a thorough association analysis of common CNVs with asthma and to identify genetic variants that influence this disease. We will perform initial association studies in a cohort of Hutterites. The Hutterites have a communal lifestyle, which greatly reduces the environmental differences among individuals and makes this population ideal for studies of complex traits. We will also conduct a thorough search for rare copy-number variants by performing whole-genome sequencing in asthmatic and non-asthmatic Hutterite individuals. Discovery of CNVs associated with asthma will lead to a better understanding of the biology of this disease and potential therapeutic targets.

Stuart B. Hooper , Ph.D. — 2010 Senior Award

Monash University

Imaging Lung Motion for Studying the Dynamics of Asthma and Its Treatments

Although most lung diseases adversely affect airflow during breathing, little is known about normal lung motion and how it is altered by disease. Current imaging techniques provide little or no information on lung motion and components of lung function, mainly because they require the lung to be still to avoid movement artefacts. We have recently shown that X-ray velocimetry can track lung tissue movement to reconstruct velocity fields that define speed and direction of regional lung motion throughout a breath. Regional maps of expansion and average time of expansion are generated which reveal lung regions with abnormal movement caused by disease. We have demonstrated the capability of this technique to detect and quantify motion within both diseased and healthy regions of lung tissue. Importantly, this technique has a higher certainty of detection of lung disease in its earliest and most subtle stages than either plethysmography or histological sections. This proposal aims to (1) exploit the regional nature of this imaging capability to gain a more detailed, regional understanding of the pathology of asthma and (2) gain previously unavailable, real-time, regional, highly-sensitive data on the efficacy of pharmacological treatment strategies as a function of both the pharmacological agent and delivery method.

Sven-Eric Jordt, Ph.D. — 2010 Extension Award

Yale University (Now at Duke University)

Sensory Chemoreceptors in Asthma and Airway Hyperresponsiveness

In our AAF-funded research we identified the sensory neuronal ion channel TRPA1 as a major determinant of the asthmatic phenotype in mice. In the murine ovalbumin (OVA) asthma model, TRPA1-deficient mice showed dramatically reduced levels of eosinophilia, goblet cell hyperplasia, cytokines and airway hyperreactivity. These effects were recapitulated by treatment of OVA wild-type mice with a TRPA1 antagonist, HC-030031. We also demonstrated efficacy of HC-030031 in the murine aspergillus asthma model. Mechanistic analysis of TRPA1-deficient mice showed diminished airway release of inflammatory neuropeptides such as CGRP. Thus, we identified TRPA1 antagonists as new anti-asthmatic agents with efficacy against multiple allergens.

The class of TRPA1 antagonists represented by HC-030031 has little oral bioavailability and lacks the specificity desired for a drug development candidate. In 2009 a novel chemical class of TRPA1 antagonists was identified, represented by A-967079 that is orally available in rodents. For our extended studies, we propose to (Aim I) examine the efficacy and potency of A-967079 in murine models of asthma. Proof of anti-asthmatic activity of two separate chemical classes of TRPA1 antagonist should provide a solid incentive for further development of TRPA1 antagonists for the treatment of asthma.

Based on our mechanistic studies we also propose to (Aim II) study the effects of novel CGRP antagonists in murine asthma models. Recently, phase III clinical trials showed promising efficacy and potency of CGRP antagonists for inflammatory pain. We hope to spur further development and clinical efforts by showing that asthma is an additional indication for CGRP antagonists.

Andre Levchenko , Ph.D. — 2010 Early Excellence Award

Johns Hopkins University (Now at Yale University)

Integrative Biology-based Investigation of Interplay between Inflammatory Signaling and Single-cell Mechanics of Human ASM

Stiffening and higher contractility of airway smooth muscle (ASM) cells can dramatically contribute to the symptomatic changes in acute asthma attacks and chronic asthma progression. The main hypothesis underlying this study is that inflammation can influence the ASM mechanics in two ways: indirectly, through fibroblast-mediated ECM remodeling. and directly, by affecting the pathways controlling ASM contractility/mechanics. These effects can be synergistic, requiring a combined treatment affecting both fibroblasts and smooth muscle cells. For instance, a combination treatment might utilize the drugs affecting not only the inflammatory stimuli, but also the signaling pathways in ASMs, including those leading to modification of cytoskeleton organization, e.g., those targeting the RhoA pathway, if these drugs can be delivered specifically. We plan to test this hypothesis by using a combination of novel techniques, relying on our experience in micro- and nano-fabrication of high-throughput and quantitative cell analysis platform, with precise delivery of biochemical and biomechanical inputs and precise measurement, analysis and modeling of the resulting data. In particular, we will mimic the ECM re-organization by nano-structuring, in a bio-mimetic fashion, the cell adhesion substrata. We will also test a battery of inflammatory stimuli for their ability to affect the biomechanical state of ASM cells and their subsequent interaction with different ECM-like structures. We will also use these platforms to screen the ability of pharmacological agents to reverse the potentially deleterious signaling and biomechanical changes in ASM cells. We anticipate that this novel, bioengineering-integrative biology approach can provide new and anticipated insights into asthma biology.

Richard M. Maizels , Ph.D. — 2010 Senior Award

University of Edinburgh

Suppression of Airway Allergy by Products of Helminth Parasites

Asthma is on the rise in the developed world, while in developing countries its prevalence remains low. Epidemiological studies have shown that asthma prevalence negatively correlates with parasitic infection, leading to the hypothesis that parasites can suppress allergic immune responses. We (and others) have previously shown that parasitic infection can suppress pathology in a mouse model of asthma. Our preliminary data show that this suppression of asthma pathology by parasite infection can be replicated by administration of the excretory/secretory products of Heligmosomoides polygyrus (HES). Therefore we hypothesize that HES contains immunomodulators that could be novel therapeutics for the treatment of asthma in humans. This research proposal aims to confirm the asthma-protective functions of HES and to dissect the mechanism of the suppression. We will examine the effects of HES on cytokine production, dendritic cells, basophils, eosinophils, macrophages and regulatory T and B cells during the initiation of asthma in vivo. Following the results of our initial experiments, we will focus on in vitro assays of affected mouse and human immune cell subsets to identify the target pathways of immunomodulatory activity in HES. We will then fractionate HES by column chromatography, and test HES fractions for immunomodulatory effects, using in vitro screens. Molecules within the immunosuppressive fractions will be identified by mass spectrometry. We will then express each candidate immunosuppressive protein in a range of transgenic systems to replicate the effects of HES with recombinant products. Successful mediators would then be available to be developed as therapeutics for human disease.

Andrew N. McKenzie , Ph.D. — 2010 Senior Award

Medical Research Council

The Role of Nuocytes in the Regulation of Asthma

Innate immunity provides the first line of defence against invading pathogens and provides important cues for the development of adaptive immunity. Type-2 immunity – responsible for protective immune responses to helminth parasites and the underlying cause of the pathogenesis of allergic asthma – consists of responses dominated by the cardinal type-2 cytokines interleukin (IL)-4, IL-5 and IL-13. T cells are an important source of these cytokines in adaptive immune responses, but innate cell sources of type-2 cytokines also exist and remain to be fully elucidated. Using novel Il13eGFP reporter mice, we have identified and functionally characterised a new innate type-2 immune effector leukocyte that we have named the nuocyte. Nuocytes expand in vivo in response to the type 2-inducing cytokines IL-25 and IL-33, and they represent the predominant early source of IL-13 during helminth infection with Nippostrongylus brasiliensis. Using the helminth infection model we have shown that, in the combined absence of IL-25 and IL-33 signalling, nuocytes fail to expand, resulting in a severe defect in worm expulsion that is rescued by the adoptive transfer of in vitro cultured wildtype, but not IL-13-deficient, nuocytes. We believe that this newly identified cell population is likely to play important and previously unappreciated roles in asthma responses by producing substantial levels of IL-13 and IL-5, and by enhancing T cell-mediated responses. We propose to investigate the roles of nuocytes in experimental asthma and so provide a foundation for our understanding of these cells in human asthma.

Carla M.P. Ribeiro , Ph.D. — 2010 Early Excellence Award

University of North Carolina, Chapel Hill

IRE1β-dependent Airway Mucin Production and ATP Release: A New Pathway in Asthma

Asthmatic airways exhibit mucin overproduction and higher levels of ATP. This application proposes a novel mechanism for mucin overproduction and tests whether it contributes to the higher ATP levels in asthma. Airway inflammation induces endoplasmic reticulum stress mediated by activation of Inositol Requiring Enzyme 1 (IRE1β or β). IRE1β is functionally relevant for Th1 cytokine secretion by airway epithelia. Our data now suggest that IRE1β is functionally important in asthma by mediating allergic airway inflammation-triggered mucin overproduction. IRE1β was only found in gut and respiratory tissues expressing mucous cells. Only Clara cells and mucous cells, but not ciliated or alveolar type II cells, expressed IRE1β. Ovalbumin-up-regulated airway mucin production was blunted in IRE1β-/- mice. A strong correlation between IRE1β and mucin production/glycosylation genes was revealed by a gene expression database. Knocking-down IRE1β in mucin-producing Calu-3 cells blunted interleukin-13-induced mucous cell metaplasia. Notably, mucin secretion and ATP release are coupled in Calu-3 cells, and ATP is localized within mucin secretory granules. Thus, IRE1β-dependent increased mucin production/storage may couple to increased ATP storage in mucin granules, and the higher ATP levels in asthmatic airways may derive from mucin granule exocytosis. Our Specific Aims will test the hypothesis that IRE1β is required for mucin production by airway mucous cells, it stimulates mucin transcription and/or regulates genes involved in mucin production or glycosylation, its over-expression potentiates mucin production, and it regulates airway ATP release by regulating the ATP content in mucin granules. These studies may reveal IRE1β as a new therapeutic target for asthma.

Thaddeus S. Stappenbeck , M.D., Ph.D. — 2010 Early Excellence Award

Washington University, St. Louis

Role of Microbial Driven Autophagy within Respiratory Airways in the Pathology of Asthma

Abnormal mucus and mucus secreting cells are an important aspect of the pathology of asthma as mucus plugging is associated with fatalities in this disease. My lab studies pathways that maintain secretory cell function in the intestinal epithelium. Our studies in this organ have uncovered a novel role for indigenous intestinal microbes that stimulate the process of autophagy in the epithelium during injury. We also found that the process of autophagy is critical for highly secretory cells such as colonic goblet cells to maintain their normal function. Thus, we have identified an interesting pathway involving microbial-driven autophagy that can counteract signals during injury that would otherwise alter mucus and mucus secreting cells. The overall goals of this proposal are to apply these ideas to the respiratory epithelium and asthma. Mucus secreting cells in the lung are distinct from intestinal goblet cells, and careful examination of the role of autophagy in respiratory mucus and comparison to the role in the intestine will be informative. We will also determine the role of autophagy in models of asthma and evaluate the role of indigenous airway microbes in their ability to stimulate autophagy in mucus secreting cells. If our overall hypothesis is supported by these studies, we will be in a position to study the mechanism by which autophagy is inhibited during lung injury and the manner in which microbes stimulate autophagy. By understanding this process, we hope to develop new ideas for therapies that can improve mucus cell function during asthma.

Kevin J. Tracey , M.D. — 2010 Senior Award

Feinstein Institute for Medical Research

Targeting Nicotinic Acetylcholine α7 Receptors in Allergic Lung Inflammation

Allergic lung inflammation is induced by exposure to environmental agents that elicit allergic inflammation and transient airway obstruction. The allergic immune response leads to inflammation characterized by infiltration of the airway mucosa with eosinophils, mast cells and lymphocytes. Persistent allergic inflammation is a hallmark of this disease. In the proposed studies we hypothesize that activation of α7 nicotinic acetylcholine receptors (α7nAChR) will attenuate allergen induced lung inflammation. In our preliminary studies we discovered that a selective agonist of the α7nAChR suppresses inflammation in standardized preclinical models including collagen induced arthritis, colitis, endotoxemia, and ischemia-reperfusion injury. To date this approach has not been studied in allergic lung inflammation. In Specific Aim 1, we will study the protective effects of a highly selective α7nAChR agonist in allergic lung inflammation. In Specific Aim 2, we will use α7nAChR knock out mice to determine the influence of α7nAChR on pathogenesis. In Specific Aim 3, using adoptive transfer experiments in knock out mice, we will determine the contribution of bone marrow derived cells to the protective effects of administering α7nAChR agonists. The proposed studies will provide important knowledge that may be used to identify new therapeutic targets for treating inflammatory lung diseases.

Dario A. Vignali , Ph.D. — 2010 Senior Award

St. Jude Children's Research Hospital (Now at University of Pittsburgh)

Interleukin-35, iTr35 and Allergic Asthma

Regulatory T cells (Tregs) can repress allergic asthma but the molecules and mechanisms used remain unknown. We have shown that interleukin-35 (IL-35: Ebi3/p35) is a potent inhibitory cytokine that is required for maximal Treg activity, can block Th2 proliferation, and has the capacity to generate Foxp3–induced regulatory T cells (iTr35) that have inhibitory activity in vivo. In this project, we will assess the capacity of IL-35 and iTr35 to control allergic asthma and will evaluate their potential as therapeutic modalities. We will utilize our extensive experience in T cell biology to pursue our first asthma research project. We will determine if allergen-specific iTr35 can protect mice from disease, thereby determining if a nature source of IL35 is sufficient to prevent and/or ameliorate allergic asthma. We will also use directed evolution by yeast surface display mutagenesis to generate highly stable IL-35 mutants that retain inhibitory activity and could be evaluated as potential therapeutics.

H. Eric Xu , Ph.D. — 2010 Senior Award

Van Andel Research Institute

Molecular Mechanism of Dissociated Glucocorticoids

Asthma is a chronic inflammatory lung disease that affects 7% of the U.S. population. Glucocorticoids are the most effective and widely used anti-inflammation drugs for the prevention and treatment of asthma, but the long-term use of glucocorticoids can cause diabetes, osteoporosis, and other unwanted side effects. While the anti-inflammation effects of glucocorticoids are mediated through the transrepression activity of the glucocorticoid receptor (GR) on major proinflammatory factors, the undesired side effects are mainly attributed to the transactivation activity of GR. Therefore, the designing of dissociated glucocorticoids that only retain the transrepression activity of GR has immense importance for the treatment of asthma, arthritis, and other inflammatory diseases. The molecular basis of how dissociated glucocorticoids work remains unclear. A lack of structural information of dissociated glucocorticoids bound to GR has hampered the discovery of the next generation of glucocorticoid drugs. Guided by new structural insights from the GR ligand binding domain (LBD), we have identified a novel compound that has the promising properties of a dissociated glucocorticoid. In this project, we propose to use molecular, structural, and chemical approaches to determine the fundamental mechanism of dissociated glucocorticoids. Our specific aims are 1) to use GR LBD mutations to dissociate transrepression from transactivation; 2) to crystallize and determine the structure of the dissociated conformation of GR that favors only transrepression; and 3) to use molecular docking to design a better dissociated glucocorticoid. Achieving these specific aims will provide a rational basis for designing the next generation of anti-inflammation drugs for treating asthma.

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