IRS phosphorylation by type I IL-4R signaling and its role in allergic disease

描述（由申请人提供）：候选人的长期职业目标是成为一名独立的科学家，其实验室是在基础分子和人类患者为基础的研究的接口。候选人强烈希望成为人类细胞中白细胞介素（IL）-4信号传导生物学各个方面的专家，以及这些途径如何导致肺部疾病，如哮喘。为了实现这些职业和研究目标，提出了三个具体目标，每个目标都是定制的，以允许进一步必要的研究培训和职业发展，最后，启动她的独立职业生涯。拟议研究的主要目的是定义IL-4与I型IL-4受体结合后的信号传导和功能反应，并了解这些信号传导途径如何促进哮喘等疾病的炎症过程。为此，将确定I型IL-4受体的独特组分（γ C链和JAK 3）在介导IRS-2（该途径中的关键衔接分子）的强酪氨酸磷酸化中的作用。 II型IL-4受体仅激发弱的IRS-2磷酸化。三个基因，交替激活的巨噬细胞的特征和与慢性肺重塑，IRS-2激活后，通过I型IL-4受体显着增强。由于IRS-2的活化对于这些基因的增强表达是关键的，因此将描述响应IL-4而负调节IRS-2的酪氨酸磷酸化的机制。SOCS蛋白、IRS-2的丝氨酸磷酸化和IRS-2乙酰化将作为候选机制进行检查。第三，I型IL-4受体信号传导在变应性疾病中的作用将通过测定来自变应性和正常供体的几种细胞类型中的受体组分表达、IL-4信号传导和IRS-2磷酸化的负调节来评估。这些变化在过敏细胞中发生的机制将被确定。通过这些研究揭示1型IL-4受体信号传导和IRS-2磷酸化下调的分子机制将对合理设计过敏性疾病（如哮喘和过敏）的治疗至关重要。

DESCRIPTION (provided by applicant): The long-term career goal of the Candidate is to become an independent scientist whose lab is at the interface of basic molecular and human patient-based research. The Candidate has a strong desire to become an expert on all aspects of the biology of interleukin (IL)-4 signaling in human cells and how these pathways lead to lung diseases, such as asthma. To achieve these career and research goals, three Specific Aims are proposed, each customized to allow the further necessary research training and career development and, finally, to launch her independent career. The broad aim of the proposed research is to define the signaling and functional responses following engagement of type I IL-4 receptors by IL-4 and to understand how these signaling pathways contribute to the inflammatory process in diseases such as asthma. To this end, the role of unique components of the type I IL-4 receptor (gammaC chain and JAK3) in mediating strong tyrosine phosphorylation of IRS-2, a key adaptor molecule in this pathway, will be defined. The type II IL-4 receptor elicits only weak IRS-2 phosphorylation. Three genes, characteristic of alternatively activated macrophages and associated with chronic remodeling of the lung, were significantly augmented after IRS-2 activation through type I IL-4 receptors. Since activation of IRS-2 is critical for the enhanced expression of these genes, the mechanisms that serve to negatively regulate the tyrosine phosphorylation of IRS-2 in response to lL-4 will be delineated. The SOCS proteins, serine phosphorylation of IRS-2 and IRS-2 acetylation will be examined as candidate mechanisms. Thirdly, the role that type I IL-4 receptor signaling plays in allergic disease will be assessed by determining receptor component expression, IL-4 signaling and negative regulation of lRS-2 phosphorylation in several cell types from allergic and normal donors. The mechanisms by which these changes occur in allergic cells will be determined. Revealing the molecular mechanisms of type 1 IL-4 receptor signaling and downregulation of IRS-2 phosphorylation by these studies will be crucial to rational design of therapies for allergic diseases, such as asthma and allergies.