Class IIa HDAC and MEF2 Targeting to Promote Foxp3+ Treg Cell Functions

 描述（由申请人提供）：两千万美国人患有自身免疫性疾病，器官移植受者有显着的移植物丢失率，并经历相当大的不良影响，从目前的免疫抑制。该项目通过关注Foxp 3 N端的关键翻译后事件来解决这些主要未满足的需求，Foxp 3是一种调节T调节细胞（Treg）发育和功能的转录因子。T细胞是调节免疫应答的核心，但是关于这些细胞的许多信息是高度描述性的，并且它们提出的治疗操作主要被设想为涉及过继细胞治疗，尽管对该方法有重大保留。我们的工作将扩展我们对Foxp 3的生化研究，并探索Foxp 3的乙酰化可以被最佳地调控的详细机制，还将评估靶向IIA类/Mef 2蛋白/蛋白相互作用的功效。 目的1将确定靶向单独IIa类HDAC相对于单独I类HDAC酶的效率。我们以前的工作表明，删除编码IIa类HDAC的基因HDAC 9，可以增强Treg在体外和体内的功能，导致的问题是，这是否可以有效地翻译为HDAC 9蛋白的靶向，以及其他IIa类HDAC酶在Treg细胞中的作用是什么？因此，我们将确定1.1）在Treg相对于常规T效应细胞（Teff）中药理学靶向IIa类HDAC酶HDAC 7的生物学和作用;和1.2）在Treg相对于常规T效应细胞（Teff）中药理学靶向IIa类HDAC酶HDAC 9的生物学和作用。 目的2将确定IIa类HDAC/Mef 2相互作用在Treg生物学中的作用。IIa类HDAC控制转录因子Mef 2的表达，并且我们的数据表明Mef 2蛋白可以结合Foxp 3启动子并且还与Foxp 3蛋白共缔合。因此，我们将确定2.1）Mef 2/Foxp 3 DNA和Mef 2/Foxp 3蛋白/蛋白相互作用在Teff中的重要性; 2.2）单个Mef 2基因的条件性缺失对Treg（和Teff）细胞的后果;和2.3）IIa类HDAC/Mef 2蛋白/蛋白相互作用的药理学靶向的治疗价值。 作为这些研究的结果， 和 * 如何以及为什么靶向Mef 2/IIa类HDACs在TcB中可以有效地促进Treg依赖的体内功能。我们的工作将产生新的见解，并可能识别出一流的分子，用于随后的自身免疫和Tx排斥临床试验的优化和评估。

 DESCRIPTION (provided by applicant): Twenty million Americans suffer from autoimmune diseases, and organ transplant recipients have significant rates of graft loss and experience considerable ill effects from current immunosuppression. This project addresses these major unmet needs by focusing on key post-translational events at the N-terminus of Foxp3, a transcription factor that regulates the development and function of T-regulatory (Treg) cells. Tregs are central to regulation of immune responses, but much of the information about these cells is highly descriptive, and their proposed therapeutic manipulation is mainly envisaged as involving adoptive cellular therapy, despite major reservations about that approach. Our work will extend our biochemical studies of Foxp3, and explore the detailed mechanisms by which acetylation of Foxp3 can optimally be pharmacologically regulated, and will also assess the efficacy of targeting class IIA/Mef2 protein/protein interactions. Aim 1 will determine the efficay of targeting of individual class IIa HDAC versus individual class I HDAC enzymes. Our previous work has shown that deletion of the gene encoding the class IIa HDAC, HDAC9, could enhance Treg function in vitro and in vivo, leading to the questions of can this be usefully translated int targeting of HDAC9 protein, and what about the roles of the other class IIa HDAC enzymes in Treg cells? Accordingly, we will determine 1.1) biology and effects of pharmacologic targeting the class IIa HDAC enzyme, HDAC7, in Treg vs. conventional T-effector (Teff) cells; and 1.2) biology and effects of pharmacologic targeting the class IIa HDAC enzyme, HDAC9, in Treg vs. conventional T-effector (Teff) cells. Aim 2 will determine the roles of class IIa HDAC/Mef2 interactions in Treg biology. Class IIa HDACs control expression of the transcription factor, Mef2, and our data indicate that Mef2 protein can bind to the Foxp3 promoter and also co-associate with Foxp3 protein. Accordingly, we will determine 2.1) the importance of Mef2/Foxp3 DNA and Mef2/Foxp3 protein/protein interactions in Tregs; 2.2) the consequences on Treg (and Teff) cells of conditional deletion of individual Mef2 genes; and 2.3) the therapeutic value of pharmacologic targeting of class IIa HDAC/Mef2 protein/protein interactions. As a result of these studies, and * how and why targeting of Mef2/class IIa HDACs in Tregs can usefully promote Treg-dependent functions in vivo. Our work will generate new insights and likely identify first-in-class molecules for subsequent optimization and evaluation in clinical trials of autoimmunity and Tx rejection.