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科学家，其实验室位于 基础分子和以患者为基础的人类研究的接口，并成为各方面的专家 人类细胞中白细胞介素4信号的生物学以及这些信号通路如何导致肺部疾病，如 作为哮喘。为了实现这些目标，提出了三个具体的分配办法，以允许进一步必要的 研究、培训和职业发展，并开始独立的职业生涯。建议的K99 职业/研究培训目标已全部实现。拟议研究的广泛目标是定义 IL-4与I型IL-4受体结合后的信号和功能反应 信号通路有助于哮喘等疾病的炎症反应。期间实现的第一个目标 K99相在DC链中定义了一个5个氨基酸(AA)的序列区间，DC链是 I型IL-4受体，介导IL-4的关键适配分子IRS-2的强酪氨酸磷酸化 发信号。该区间介于aa318和323之间，并与激活的JAK3在 信号复合体。交替激活的巨噬细胞的三个基因及其相关基因 慢性肺重塑，通过I型IL-4激活IRS-2后显著增强 感受器。由于IRS-2的激活对于增强这些基因的表达至关重要，因此 在RoO阶段执行的第二个目标将是描述起消极作用的机制 调节IL-4对IRS-2酪氨酸磷酸化的影响。SOCS蛋白与丝氨酸 IRS-2的磷酸化将被视为候选机制。第三，I型IL-4的作用 将通过测定受体组分的表达来评估受体信号在过敏性疾病中的作用。 IL-4信号转导和IRS-2磷酸化负调控在变态反应性和正常人几种细胞中的表达 捐赠者。这些变化发生在过敏细胞中的机制将被确定。揭示了 I型IL-4受体信号转导及下调LRS-2磷酸化的分子机制 这些研究将对合理设计哮喘等过敏性疾病的治疗方案至关重要。

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.