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：由CD4+T淋巴细胞产生的细胞因子在宿主适应性免疫反应中发挥重要作用，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淋巴细胞产生细胞因子的途径的了解还不完全。我们已经确定了一种调节CD4+T细胞产生细胞因子的新途径，使用的分子被认为主要涉及神经细胞功能和阿尔茨海默病的发病机制。我们发现，缺乏细胞外基质(ECM)蛋白F-响应蛋白或其受体apoE受体2(ApoER2)的CD4+T细胞表现出细胞因子产生缺陷，而缺乏F-响应蛋白的小鼠哮喘的发展被减弱。我们的总体假设是，F-响应蛋白及其受体ApoER2和淀粉样蛋白-2前体蛋白(APP)构成了一对新的配体-受体对，它们在CD4+T细胞表面的相互作用为启动细胞因子的产生提供了关键信号。为了验证这一假说，我们提出了两个特定的目标：1.建立F-Respondin调节CD4+T淋巴细胞细胞因子产生的机制。2.检测ApoER2和APP介导的信号通路在CD4+T细胞产生细胞因子中的作用。这些研究的结果不仅将为调节CD4+T淋巴细胞细胞因子的产生和哮喘的发生提供重要的机制见解，而且还可能导致发现治疗哮喘的新的药物靶点。考虑到目前工业界和学术界正在努力开发阿尔茨海默病的治疗方法，我们提议的研究可能能够将为阿尔茨海默病开发的药物重新用于哮喘治疗。项目叙事 由CD4+T淋巴细胞产生的细胞因子参与了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生的途径的了解仍然不完整。对调节细胞因子产生和哮喘发生的途径的研究将导致新的发现，这将有助于哮喘治疗的药物设计。我们最近的工作发现了一条新的途径，通过调节CD4+T细胞中细胞因子的产生和小鼠哮喘的发展，这些分子被认为主要参与神经细胞功能和阿尔茨海默病的发病机制。鉴于目前工业界和学术界在开发阿尔茨海默病治疗方法方面所做的努力，我们拟议的研究可能能够将为阿尔茨海默病开发的药物重新用于哮喘治疗。