Identifying Novel Ion Channels Regulating T cell Function

识别调节 T 细胞功能的新型离子通道

• 批准号: 9297218
• 负责人: STEFAN FESKE
• 金额: $ 21.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9297218
• 关键词: Adoptive Transfer; Applications Grants; Area; Autoimmune Diseases; Autoimmunity; Bioinformatics; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Calcium; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Carrier Proteins; Cell membrane; Cell physiology; Cells; Cellular Immunity; Chlorides; Data; Databases; Development; Drug Targeting; Employee Strikes; Epstein-Barr Virus Infections; Future; Genes; Genetic; Goals; Grant; Human; Hypersensitivity; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunology; Impairment; In Vitro; Infection; Inflammation; Inherited; Ion Channel; Ions; Kidney; Knowledge; Lead; Libraries; Lymphocyte Function; Lymphocytic choriomeningitis virus; Magnesium; Mediating; Membrane; Membrane Potentials; Movement; Mus; Mutation; Natural Killer Cells; Nervous system structure; Patients; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiology; Play; Potassium; Potassium Channel; Proteins; Reagent; Reporting; Research; Role; STIM1 gene; Sodium; Sodium Chloride; T cell regulation; T cell response; T-Cell Development; T-Lymphocyte; Technology; Therapeutic; Tissues; Tumor Immunity; Virus Diseases; Zinc; antiviral immunity; base; body system; cell mediated immune response; cell type; comparative; design; differential expression; driving force; experience; experimental study; follow-up; functional genomics; genetic regulatory protein; in vivo; inhibitor/antagonist; insight; knock-down; lipophilicity; neglect; next generation sequencing; novel; response; screening; small hairpin RNA; targeted treatment; transcription factor; tumor

Project Summary The goal of this application is to identify novel ion channels that regulate the function of T lymphocytes. T cells play an important role in immune responses to infection and mediate inflammation in a variety of autoimmune diseases. The function of T cells has been reported to depend on ion channels that control their development, proliferation and effector functions. More than 600 ion channels and associated proteins regulate the movement of a ions, including calcium, magnesium, zinc, potassium, sodium and chloride, across lipophilic cell membranes. The role of ion channels is well studied in cells of the nervous and cardiovascular system or the kidney. By comparison, relatively little is known about ion channels in the immune system and how they regulate normal immunity to infection or abnormal immune responses in allergy or autoimmune diseases. Of the more than 600 known ion channels and associated proteins, only 8-10 are well established to regulate the function of T cells based on genetic evidence in humans and mice. This is a major gap in our knowledge of T cell physiology and the regulation of T cell immunity. We therefore propose to analyze novel ion channels that have not been associated with T cell function before and that we found to be highly and differentially expressed in human and mouse T cells based on comparative bioinformatics analyses. We furthermore propose to conduct a functional genomics screen to identify novel ion channels that regulate T cell function in the context of viral infection in vivo. A systematic analysis of ion channels in T cell or other immune responses has never been done. This striking void at the interface of immunology and physiology represents a discovery opportunity to define ion channels that regulate T cell mediated immunity to infection and autoimmunity. From a translational perspective, ion channel inhibitory drugs have successfully been used to treat diseases of the cardiovascular and nervous systems, proving the usefulness of ion channels as drug targets. The identification of novel ion channels that control T cell immunity has significant therapeutic potential for the treatment of immune diseases. Such ion channels would be promising drug targets for the treatment of T cell-mediated immune diseases such as autoimmune disorders or allergy or for the modulation of T cell function in antitumor immunity. Although our initial screen will focus on ion channels that regulate CD4+ T cell-mediated immunity to infection, future screens using similar approaches will be designed to identify ion channels that control the function of T cells in autoimmunity and antitumor immunity. Beyond the immune system, the screening approach we propose here can be applied to identify novel ion channels that regulate the function of many other tissues and cell types. The reagents, data and experience gathered through this R21 grant will open new research avenues for our lab and lead to future R01 grant applications.

项目摘要 这项应用的目标是识别调节T淋巴细胞功能的新离子通道。T细胞 在多种自身免疫性疾病中对感染的免疫反应和介导炎症起重要作用 疾病。据报道，T细胞的功能依赖于控制其发育的离子通道， 增殖和效应器功能。600多个离子通道和相关蛋白质调节着 钙、镁、锌、钾、钠和氯化物离子在亲脂细胞中的运动 膜。离子通道的作用在神经系统和心血管系统的细胞中得到了很好的研究 肾脏。相比之下，人们对免疫系统中的离子通道以及它们是如何形成的知之甚少 调节对感染的正常免疫或过敏或自身免疫性疾病的异常免疫反应。的 在600多个已知的离子通道和相关蛋白中，只有8-10个被很好地建立来调节 基于人类和小鼠遗传证据的T细胞功能。这是我们对T的认识上的一个重大差距 细胞生理学与T细胞免疫调节。因此，我们建议分析新的离子通道 以前没有发现与T细胞功能相关的基因，我们发现它们是高表达和差异表达的 基于比较生物信息学分析的人类和小鼠T细胞。此外，我们建议 进行功能基因组学筛选，以确定在上下文中调节T细胞功能的新离子通道 体内病毒感染的可能性。对T细胞或其他免疫反应中的离子通道进行系统分析 已经做完了。免疫学和生理学交界处的这一惊人的空白代表着一个发现的机会 明确调节T细胞介导的感染免疫和自身免疫的离子通道。从一个 从翻译的角度来看，离子通道抑制药物已成功地用于治疗慢性阻塞性肺疾病 心血管和神经系统，证明离子通道作为药物靶点的有用性。身份识别 控制T细胞免疫的新型离子通道具有显著的治疗潜力 免疫性疾病。这种离子通道有望成为治疗T细胞介导性白血病的药物靶点 自身免疫性疾病或过敏或T细胞功能调节在抗肿瘤中的作用 豁免权。尽管我们最初的筛选重点是调节CD4+T细胞介导的免疫的离子通道 感染，未来使用类似方法的筛查将被设计成识别控制 T细胞在自身免疫和抗肿瘤免疫中的作用在免疫系统之外，筛查 我们在这里提出的方法可以用来识别调节许多 其他组织和细胞类型。通过这笔R21赠款收集的试剂、数据和经验将开启新的 为我们的实验室研究途径，并导致未来的R01拨款申请。