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

IRS 磷酸化 I 型 IL-4R 信号及其在过敏性疾病中的作用

• 批准号: 8332322
• 负责人: NICOLA M HELLER
• 金额: $ 24.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8332322
• 关键词: 2-tyrosine; Acetylation; Allergic; Allergic Disease; Allergic inflammation; Amino Acid Sequence; Asthma; Award; Biological Assay; Biology; Cells; Characteristics; Chronic; Co-Immunoprecipitations; Complex; Cytokine Inducible SH2-Containing Protein; Cytoplasmic Tail; Data; Disease; Down-Regulation; Environment; Epithelium; Extrinsic asthma; Fibroblasts; Gene Expression; Genes; Goals; Hematopoietic; Human; In Vitro; Individual; Inflammation; Inflammatory; Instruction; Insulin; Insulin-Like Growth Factor I; Interleukin-4; JAK2 gene; JAK3 gene; Janus kinase; Janus kinase 3; Lead; Link; Lung; Lung diseases; Mediating; Molecular; Mus; Ovalbumin; Pathogenesis; Pathway interactions; Patients; Phase; Phosphorylation; Phosphotransferases; Play; Post-Translational Protein Processing; Proteins; Receptor Signaling; Recruitment Activity; Regulation; Research; Research Training; Role; Scientist; Serine; Signal Pathway; Signal Transduction; Signaling Protein; TYK2; Testing; Therapeutic; Translating; Tyrosine Phosphorylation; Up-Regulation; arginase; base; career; career development; cell type; design; inhibitor/antagonist; insulin receptor substrate-2 protein; macrophage; meetings; monocyte; mutant; receptor; receptor downregulation; receptor expression; response; therapeutic target; therapy design

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.

候选人的长期职业目标是成为一名独立科学家，其实验室正在 基本分子和人类基于患者的研究的界面，并成为各个方面的专家 人类细胞中Interieukin（IL）-4信号传导的生物学以及这些途径如何导致肺部疾病，这样 作为哮喘。为了实现这些目标，提出了三个特定的施舍，以便进一步必要 研究培训和职业发展并启动她的独立职业。拟议的K99 职业/研究培训目标都得到了满足。拟议研究的广泛目的是定义 IL-4的I型LL-4受体参与后的信号传导和功能响应以及如何 信号通路会导致诸如哮喘等疾病的炎症。在 K99相定义了DC链中的5个氨基酸（AA）序列间隔， I型IL-4受体，介导了IRS-2的强酪氨酸磷酸化，IRS-2是IL-4中的关键衔接子分子 信号。间隔位于AA318和323之间，与激活的Jak3的关联相关 信号复合物。三个基因，特征的特征是替代激活的巨噬细胞和相关的 通过肺的慢性重塑，通过I型IL-4激活IRS-2激活后显着增强 受体。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阶段进行的第二个目标将是描述有效的机制 根据IL-4的响应，调节IRS-2的酪氨酸磷酸化。 SOCS蛋白质和丝绸 IRS-2的磷酸化将被检查为候选机制。第三，I型IL-4的作用 通过确定受体成分表达，将评估过敏性疾病中的受体信号传导。 IL-4信号传导和irs-2磷酸化的阴性调节性来自过敏和正常的几种细胞类型 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受体信号传导的分子机制和LRS-2磷酸化的下调 这些研究对于哮喘等过敏性疾病的理性设计至关重要。