tate the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. Allergic asthma is a chronic disease which has been on the rise in recent decades. Although the etiology of asthma is not well understood, it is currently thought to arise as a result of inappropriate CD4+Th2-mediated inflammatory responses to airborne allergens in susceptible individuals. Despite extensive investigation, the exact mechanisms responsible for the initiation of Th2 (IL-13) immune responses in asthmatic individuals are unknown. The initiation and maintenance of Th2 immune responses are dependent upon specific activation of dendritic cells at the airway surface. Recent evidence suggests that specific subsets of dendritic cells (DCs) are critical for the initiation of allergic airway responses and play an important role in driving either immunity (myeloid, mDCs) or tolerance (plasmacytoid, pDCs) to inhaled antigens. However, the mechanisms by which specific DC subsets are recruited to the lung and activated in response to allergen exposure are unknown. Our preliminary data collectively upport the novel hypothesis that the common allergen, house dust mite, triggers the rapid release of the immature dendritic cell chemoattractant, CCL20, from its storage sites on the extracellular matrix molecule syndecan-1, through the activation of dectin-1, a pattern recognition molecule which recognizes beta-glucans. CCL20 once released drives the preferential recruitment and activation of the immunogenic myeloid dendritic cell subset which in turn directs Th2 cell differentiation and the development of allergic inflammation. Moreover, IL-13 itself can induce the release of CCL20 from the airway epithelium providing an amplication loop for continued Th2 cytokine production. The molecular mechanisms driving epithelial CCL20 release from syndecan, the mechanisms of preferential recruitment and activation of mDCs by CCL20/syndecan-1, the mechanisms by which IL-13 induces CCL20 release and perpetuates dendritic cell recruitment into the lung, and the exact contributions of these pathways to allergen-induced airway hyperresponsiveness and airway inflammation are unknown. Thus we propose the following specific aims to test this hypothesis and define the molecular mechanisms underlying allergen-induced induction of Th2 cytokine production: 1)To determine the role of dectin-1 signaling pathways in the HDM-induced release of syndecan-1/CCL20 complexes from the surface of airway epithelial cells;2) To determine the mechanism by which syndecan-1 regulates dendritic cell conditioning of T cell IL- 13 production in vitro and in vivo;3)To determine the mechanisms by which IL-13 perpetuates the recruitment of immunogenic DC subsets and further Th2 cytokine production. Collectively, the results of these studies should provide a better understanding of the mechanisms driving Th2 (IL-13) cytokine production and may lead to the development of novel asthma therapies which are disease modifying rather than ameliorative. PERFORMANCE SITE(S) (organization, city, state) Children's Hospital Medical Center Cincinnati, OH KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project Wills-Karp, Marsha Wildc7 CCHMC PI Finkelman, Fred frefin CCHMC Co-Investigator
Asthma is a chronic disease of the lung which has been on the rise in recent decades. As IL-13 has been shown to be a central mediator of allergic inflammation, studies in this proposal aim to elucidate the pathways leading to the generation of IL-13 in the lung. The identification of specific pathways initiating these these responses may lead to the development of novel, effective therapies for the treatment of this ever-increasing disease.
|Lajoie, S; Lewkowich, I; Herman, N S et al. (2014) IL-21 receptor signalling partially mediates Th2-mediated allergic airway responses. Clin Exp Allergy 44:976-85|
|Lajoie, Stephane; Wills-Karp, Marsha (2013) New twist on an ancient innate immune pathway. Immunity 39:1000-2|
|Wills-Karp, Marsha (2010) Allergen-specific pattern recognition receptor pathways. Curr Opin Immunol 22:777-82|
|Wills-Karp, M; Nathan, A; Page, K et al. (2010) New insights into innate immune mechanisms underlying allergenicity. Mucosal Immunol 3:104-10|
|Lajoie, Stephane; Lewkowich, Ian P; Suzuki, Yusuke et al. (2010) Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol 11:928-35|
|Lewkowich, Ian P; Lajoie, Stephane; Clark, Jennifer R et al. (2008) Allergen uptake, activation, and IL-23 production by pulmonary myeloid DCs drives airway hyperresponsiveness in asthma-susceptible mice. PLoS One 3:e3879|