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

IIa 类 HDAC 和 MEF2 靶向促进 Foxp3 Treg 细胞功能

• 批准号: 9079672
• 负责人: Wayne William Hancock
• 金额: $ 42万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9079672
• 关键词: Acetylation; Address; Adrenal Cortex Hormones; Affect; American; Atherosclerosis; Autoimmune Diseases; Autoimmunity; Behavior; Binding; Binding Sites; Biochemical; Biology; Blocking Antibodies; C-terminal; CTLA4-Ig; Calcium/calmodulin-dependent protein kinase; Canis familiaris; Cell physiology; Cells; Chronic; Clinical Trials; Complex; Congresses; Cytoplasm; DNA; DNA Binding; Data; Deacetylase; Deacetylation; Development; Disease; Docking; EP300 gene; Effector Cell; Enzymes; Evaluation; Event; Gene Deletion; Genes; Genetic; Genetic study; Goals; Graft Rejection; HDAC4 gene; HDAC7 histone deacetylase; HDAC9 gene; Histone Acetylation; Histones; Immune; Immune System Diseases; Immune response; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Individual; Inflammatory Bowel Diseases; Infusion procedures; Knowledge; Literature; Long-Term Effects; Maintenance; Mediating; Molecular; Monoclonal Antibody Therapy; Muscle; National Institute of Allergy and Infectious Disease; Neoplasm Transplantation; Neurons; Nuclear Export; Organ Transplantation; Pathogenesis; Patients; Play; Post-Translational Protein Processing; Proteins; Reagent; Recruitment Activity; Regulation; Regulatory T-Lymphocyte; Reporting; Research Support; Reservations; Response Elements; Role; Safety; Signal Transduction; Site; T-Lymphocyte; TNF gene; Testing; Therapeutic; Translating; Translational Research; Transplant Recipients; Treatment Efficacy; Wild Type Mouse; Work; allograft rejection; clinically relevant; experience; histone acetyltransferase; in vivo; insight; knock-down; myocyte-specific enhancer-binding factor 2; nephrotoxicity; non-histone protein; novel therapeutics; promoter; protein protein interaction; public health relevance; selective expression; thymocyte; transcription factor; translational study

 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.

 描述(申请人提供)：2000万美国人患有自身免疫性疾病，器官移植接受者的移植物损失率很高，并经历了当前免疫抑制的相当大的不良影响。该项目通过关注Foxp3 N末端的关键翻译后事件来满足这些主要的未得到满足的需求，Foxp3是一种调节T调节(Treg)细胞的发育和功能的转录因子。Treg是调节免疫反应的中心，但关于这些细胞的许多信息都是高度描述性的，尽管对这种方法有很大的保留意见，但他们提出的治疗操作主要被设想为涉及过继细胞治疗。我们的工作将扩展我们对Foxp3的生化研究，探索Foxp3乙酰化可以最佳药理学调节的详细机制，并将评估靶向IIA/Mef2类蛋白质/蛋白质相互作用的有效性。目标1将确定靶向单个IIa类HDAC酶与单个I类HDAC酶的效果。我们以前的工作表明，缺失编码IIa HDAC类HDAC9的基因可以在体外和体内增强Treg的功能，这导致了这样的问题：这是否可以有效地翻译为靶向HDAC9蛋白，以及其他IIa HDAC酶在Treg细胞中的作用如何？因此，我们将确定1.1)生物学和药物靶向IIa类HDAC酶HDAC7在Treg细胞和传统T效应(TEff)细胞中的作用；以及1.2)生物学和药物靶向IIa HDAC酶HDAC9在Treg和传统T效应(Tef)细胞中的作用。目标2将确定IIa类HDAC/MEF2相互作用在Treg生物学中的作用。IIa类HDAC控制转录因子Mef2的表达，我们的数据表明Mef2蛋白可以与Foxp3启动子结合，也可以与Foxp3蛋白共结合。因此，我们将确定2.1)Mef2/Foxp3 DNA和Mef2/Foxp3蛋白/蛋白质相互作用在Treg中的重要性；2.2)有条件地缺失单个Mef2基因对Treg(和Tef)细胞的影响；以及2.3)IIa类HDAC/Mef2蛋白质/蛋白质相互作用的药理学靶向的治疗价值。作为这些研究的结果，以及*在Treg中靶向Mef2/Class IIa HDAC如何以及为什么能够有效地促进体内Treg依赖功能。我们的工作将产生新的见解，并可能识别一流的分子，以便在自身免疫和TX排斥的临床试验中进行后续的优化和评估。