A novel pathway regulating cytokine production and asthma development

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CD4+ T淋巴细胞中调节细胞因子产生的途径的理解仍然不完整。我们发现了一种调节CD4+ T细胞细胞因子产生的新途径，该途径使用的分子被认为主要参与阿尔茨海默病的神经元细胞功能和发病机制。我们发现，缺乏细胞外基质（ECM）蛋白F-spondin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，缺乏F-spondin的小鼠哮喘发展减弱。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一个关键信号。为了验证这一假设，我们提出了两个具体目标：1。探讨F-spondin调节CD4+ T淋巴细胞细胞因子产生的机制。2. 探讨ApoER2和APP介导的CD4+ T淋巴细胞细胞因子产生的信号通路。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展的调控提供重要的机制见解，而且可能导致哮喘治疗的新药物靶点的发现。鉴于目前工业界和学术界都在努力开发阿尔茨海默病的治疗方法，我们提出的研究可能能够将为阿尔茨海默病开发的药物转向哮喘治疗。项目的叙述

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.