Identifying Novel Ion Channels Regulating T cell Function

项目摘要 本申请的目的是鉴定调节T淋巴细胞功能的新型离子通道。T细胞 在对感染的免疫应答中起重要作用，并在多种自身免疫性疾病中介导炎症。 疾病据报道，T细胞的功能取决于控制其发育的离子通道， 增殖和效应子功能。超过600种离子通道和相关蛋白调节着细胞的功能。 包括钙、镁、锌、钾、钠和氯离子在内的a离子穿过亲脂性细胞的运动 膜。离子通道的作用在神经和心血管系统的细胞或神经细胞中得到了充分的研究。 肾相比之下，对免疫系统中的离子通道以及它们如何影响免疫系统的了解相对较少。 调节对感染的正常免疫或过敏或自身免疫性疾病中的异常免疫应答。的 在已知的600多种离子通道和相关蛋白质中，只有8-10种被很好地确立来调节 基于人类和小鼠遗传证据的T细胞功能。这是我们对T 细胞生理学和T细胞免疫调节。因此，我们建议分析新的离子通道， 以前与T细胞功能无关，我们发现它在T细胞中高度表达， 在人类和小鼠T细胞的基础上比较生物信息学分析。我们还建议， 进行功能基因组学筛选，以鉴定在背景下调节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的离子通道的系统分析从未 已经完成了。在免疫学和生理学的交界处，这种惊人的空白代表了一个发现的机会。 确定调节T细胞介导的对感染和自身免疫的免疫的离子通道。从 从翻译的角度来看，离子通道抑制药物已成功地用于治疗糖尿病性疾病。 心血管和神经系统，证明了离子通道作为药物靶点的有用性。识别 控制T细胞免疫的新型离子通道的发现对于治疗 免疫疾病。这种离子通道将是治疗T细胞介导的肿瘤的有前景的药物靶点。 免疫疾病如自身免疫性疾病或变态反应或用于调节抗肿瘤中的T细胞功能 免疫力虽然我们最初的筛选将集中在调节CD 4 + T细胞介导的免疫的离子通道上， 感染，未来的屏幕使用类似的方法将被设计来识别离子通道，控制 T细胞在自身免疫和抗肿瘤免疫中的功能。除了免疫系统， 我们在这里提出的方法可以用于识别新的离子通道，调节许多功能， 其他组织和细胞类型。通过R21赠款收集的试剂，数据和经验将打开新的 为我们的实验室的研究途径，并导致未来的R 01赠款申请。

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.