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

候选人的长期职业目标是成为一名独立的科学家，其实验室位于 基础分子和人类患者为基础的研究接口，并成为各方面的专家， 人类细胞中白细胞介素（IL）-4信号传导的生物学以及这些途径如何导致肺部疾病， 哮喘。为了实现这些目标，提出了三个具体的施舍，以允许进一步必要的 研究培训和职业发展，并开始她的独立职业生涯。建议的K99 职业/研究培训目标均已实现。拟议研究的主要目的是确定 IL-4与I型IL-4受体结合后的信号传导和功能反应以及这些反应如何发生 信号传导途径导致疾病如哮喘中的炎症。第一个目标是在 K99期在DC链内限定了5个氨基酸（aa）的序列间隔，DC链的一个组分是K99期。 I型IL-4受体，介导IRS-2的强酪氨酸磷酸化，IRS-2是IL-4中的关键衔接分子 发信号。该间隔位于aa 318和323之间，并与激活的JAK 3在 信号复合体三个基因，交替激活的巨噬细胞的特征和相关的 在IRS-2通过I型IL-4激活后， 受体。由于IRS-2的激活对于这些基因的增强表达至关重要，因此， 在ROO阶段要实现的第二个目标是描述那些消极地 调节IRS-2的酪氨酸磷酸化以响应IL-4。SOCS蛋白和丝氨酸 IRS-2的磷酸化将作为候选机制进行研究。第三，I型IL-4的作用 通过测定受体组分的表达来评估受体信号传导在变应性疾病中的作用， IL-4信号转导和IRS-2磷酸化在过敏和正常细胞中的负调节 捐助者。这些变化在过敏细胞中发生的机制将被确定。揭示 I型IL-4受体信号传导和通过IL-4受体下调IRS-2磷酸化的分子机制 这些研究对于合理设计过敏性疾病如哮喘的治疗方法至关重要。

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 and to become an expert on all aspects of the biology of interieukin (IL)-4 signaling in human cells and how these pathways lead to lung diseases, such as asthma. To achieve these goals, three Specific Alms were proposed, to allow the further necessary research training and career development and to launch her independent career. The proposed K99 career/research training goals have all been met. The broad aim of the proposed research is to define the signaling and functional responses following engagement of type I lL-4 receptors by IL-4 and how these signaling pathways contribute to inflammation in diseases such as asthma. The first Aim achieved during the K99 phase defined a 5 amino acid (aa) sequence interval within the DC chain, one component of the type I IL-4 receptor, that mediated strong tyrosine phosphorylation of IRS-2, a key adaptor molecule in IL-4 signaling. The interval lay between aa318 and 323 and correlated with the association of activated JAK3 in the signaling complex. 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 goal of the second Aim to be carried out in the ROO phase will be to delineate the mechanisms that serve to negatively regulate the tyrosine phosphorylation of IRS-2 in response to IL-4. The SOCS proteins and serine phosphorylation of IRS-2 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 regulatioii of IRS-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 I IL-4 receptor signaling and downregulation of lRS-2 phosphorylation by these studies will be crucial to rational design of therapies for allergic diseases, such as asthma.