A novel pathway regulating cytokine production and asthma development

调节细胞因子产生和哮喘发展的新途径

• 批准号: 7356481
• 负责人: You-Wen He
• 金额: $ 23.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7356481
• 关键词: Academia; Allergic; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Asthma; Attenuated; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cell surface; Development; Disease; Drug Delivery Systems; Drug Design; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Helper-Inducer T-Lymphocyte; Immune response; Industry; Investigation; LDL-Receptor Related Protein 1; Lead; Ligands; Mediating; Mus; Neurons; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Play; Production; Protein Precursors; Receptor-CD3 Complex, Antigen, T-Cell; Regulation; Research; Role; Signal Pathway; Signal Transduction; T-Lymphocyte; Testing; Work; cytokine; insight; novel; pathogen; receptor

DESCRIPTION: Cytokines produced by CD4+ T lymphocytes play essential roles in host adaptive immune responses and are involved in the development of allergic diseases including asthma. Our understanding of the pathways regulating cytokine production in CD4+ T lymphocytes remains incomplete. We have identified a novel pathway regulating cytokine production in CD4+ T cells using molecules that are thought to be primarily involved in neuronal cell function and pathogenesis of Alzheimer's disease. We show that CD4+ T cells lacking the extracellular matrix (ECM) protein F-spondin or its receptor apoE receptor 2 (ApoER2) exhibit defective cytokine production, and asthma development is attenuated in mice lacking F-spondin. Our overall hypothesis is that F-spondin and its receptors ApoER2 and amyloid-2 precursor protein (APP) constitute a novel ligand-receptor pairs whose interaction on the CD4+ T cell surface provides a critical signal to initiate cytokine production. To test this hypothesis, we propose two specific aims: 1. To establish the mechanisms by which F-spondin regulates CD4+ T lymphocyte cytokine production. 2. To examine the signaling pathway mediated by ApoER2 and APP in CD4+ T lymphocyte cytokine production. Results from these studies will not only provide important mechanistic insights into the regulation of CD4+ T lymphocyte cytokine production and asthma development, but also may lead to discoveries of novel drug targets for asthma treatment. Given the current effort by industry and academia to develop Alzheimer's disease treatments, our proposed research may be able to redirect the drugs developed for Alzheimer's disease into asthma treatment. Project Narrative Cytokines produced by CD4+ T lymphocytes are involved in the development of allergic diseases including asthma. Our understanding of the pathways regulating cytokine production and asthma development remains incomplete. Investigation of the pathways regulating cytokine production and asthma development will lead to new discoveries that will help drug designs for asthma treatment. Our recent work has identified a novel pathway regulating cytokine production in CD4+ T cells and asthma development in mice by molecules that are thought to be primarily involved in neuronal cell function and pathogenesis of Alzheimer's disease. Given the current effort in the development of Alzheimer's disease treatment by industry and academia, our proposed research may be able to redirect the drugs developed for Alzheimer's disease into asthma treatment.

描述：CD4+ T淋巴细胞产生的细胞因子在宿主适应性免疫反应中起着重要作用，并参与包括哮喘在内的过敏性疾病的发展。我们对调节CD4+ T淋巴细胞中细胞因子产生的途径的理解仍然不完整。我们已经确定了一种新的途径，该途径使用被认为主要参与神经元细胞功能的分子和阿尔茨海默氏病的发病机理，从而调节CD4+ T细胞中细胞因子的产生。我们表明，缺乏细胞外基质（ECM）蛋白F-蛋白质或其受体APOE受体2（APOER2）的CD4+ T细胞表现出缺乏F-Spondin的小鼠中的细胞因子产生缺陷，并且哮喘发育受到减弱。我们的总体假设是，F-Spondin及其受体ApoER2和淀粉样蛋白-2前体蛋白（APP）构成了一种新型的配体 - 受体对，其在CD4+ T细胞表面上的相互作用为引发细胞因子的产生提供了关键的信号。为了检验这一假设，我们提出了两个具体的目的：1。建立F-Spondin调节CD4+ T淋巴细胞细胞因子产生的机制。 2。检查CD4+ T淋巴细胞细胞因子产生中ApoER2和APP介导的信号传导途径。这些研究的结果不仅将为CD4+ T淋巴细胞细胞因子产生和哮喘发育的调节提供重要的机理见解，而且还可能导致发现新型药物靶标的哮喘治疗的发现。鉴于工业和学术界目前为发展阿尔茨海默氏病治疗的努力，我们提出的研究可能能够将为阿尔茨海默氏病开发的药物重定向到哮喘治疗中。项目叙述 CD4+ T淋巴细胞产生的细胞因子参与包括哮喘在内的过敏性疾病的发展。我们对调节细胞因子产生和哮喘发育的途径的理解仍然不完整。调查调节细胞因子产生和哮喘发育的途径将导致新发现，这将有助于药物设计进行哮喘治疗。我们最近的工作已经确定了一种新的途径，该途径通过被认为主要参与阿尔茨海默氏病的神经元细胞功能和发病机理的分子来调节CD4+ T细胞和小鼠哮喘发育的细胞因子产生。鉴于目前通过行业和学术界开发阿尔茨海默氏病治疗的努力，我们提出的研究可能能够将为阿尔茨海默氏病开发的药物重定向到哮喘治疗中。