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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

基本信息

批准号：
8722259
负责人：
NICOLA M HELLER
金额：
$ 5.66万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8722259
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

项目摘要

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.

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人类患者研究的接口，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，例如如哮喘。为了实现这些目标，提出了三项具体救济措施，以便进一步开展必要的工作研究培训和职业发展并开始她的独立职业生涯。拟议的K99 职业/研究培训目标均已实现。拟议研究的主要目标是定义 IL-4 与 I 型 IL-4 受体结合后的信号传导和功能反应以及这些反应如何信号通路会导致哮喘等疾病的炎症。期间实现的第一个目标 K99 相定义了 DC 链内的 5 个氨基酸 (aa) 序列间隔，DC 链的一个组成部分 I 型 IL-4 受体，介导 IRS-2 的强酪氨酸磷酸化，IRS-2 是 IL-4 中的关键接头分子发信号。该间隔位于 aa318 和 323 之间，并且与激活的 JAK3 的关联相关。信号复合体。三个基因，交替激活巨噬细胞的特征和相关随着肺的慢性重塑，IRS-2 通过 I 型 IL-4 激活后显着增强受体。由于 IRS-2 的激活对于这些基因的增强表达至关重要，因此原产地规则阶段要实现的第二个目标是界定产生负面影响的机制调节 IRS-2 响应 IL-4 的酪氨酸磷酸化。 SOCS 蛋白和丝氨酸 IRS-2 的磷酸化将作为候选机制进行研究。三、I型IL-4的作用受体信号传导在过敏性疾病中的作用将通过确定受体成分表达来评估，过敏性和正常的几种细胞类型中 IL-4 信号传导和 IRS-2 磷酸化的负调节捐助者。过敏细胞中发生这些变化的机制将被确定。揭示 I 型 IL-4 受体信号传导和 IRS-2 磷酸化下调的分子机制这些研究对于合理设计哮喘等过敏性疾病的疗法至关重要。