Identifying Novel Ion Channels Regulating T cell Function

识别调节 T 细胞功能的新型离子通道

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该应用的目标是识别调节 T 淋巴细胞功能的新型离子通道。 T细胞在对感染的免疫反应中发挥重要作用，并介导多种自身免疫性疾病的炎症疾病。据报道，T 细胞的功能取决于控制其发育的离子通道，增殖和效应器功能。超过 600 个离子通道和相关蛋白质调节离子（包括钙、镁、锌、钾、钠和氯）穿过亲脂细胞的运动膜。离子通道的作用在神经和心血管系统的细胞或肾。相比之下，人们对免疫系统中的离子通道及其如何发挥作用的了解相对较少。调节对感染的正常免疫力或过敏或自身免疫性疾病的异常免疫反应。的超过 600 种已知的离子通道和相关蛋白，只有 8-10 种已被确定可以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 知识的一个重大差距细胞生理学和 T 细胞免疫的调节。因此，我们建议分析新的离子通道之前未发现与 T 细胞功能相关，但我们发现其表达高度差异化基于比较生物信息学分析的人类和小鼠 T 细胞。我们还建议进行功能基因组学筛选，以确定在环境中调节 T 细胞功能的新型离子通道体内病毒感染。对 T 细胞或其他免疫反应中离子通道的系统分析从未已经完成了。免疫学和生理学界面上的这一惊人空白代表了一个发现机会定义调节 T 细胞介导的感染和自身免疫免疫的离子通道。来自一个从转化的角度来看，离子通道抑制药物已成功用于治疗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。鉴定控制 T 细胞免疫的新型离子通道对于治疗以下疾病具有显着的治疗潜力免疫疾病。这种离子通道将成为治疗 T 细胞介导的疾病的有希望的药物靶点。免疫疾病，如自身免疫性疾病或过敏或调节 T 细胞功能抗肿瘤免疫。尽管我们的初始筛选将重点关注调节 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屏幕将被设计来识别控制感染的离子通道 T细胞在自身免疫和抗肿瘤免疫中的功能。除了免疫系统之外，筛查我们在这里提出的方法可用于识别调节许多功能的新型离子通道其他组织和细胞类型。通过 R21 资助收集的试剂、数据和经验将开辟新的领域我们实验室的研究途径，并导致未来的 R01 资助申请。