Immune chemistry and therapeutic features of FOXP3

FOXP3 的免疫化学和治疗特征

• 批准号: 7653662
• 负责人: MARK I GREENE
• 金额: $ 140.35万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653662
• 关键词: Immune; chemistry; therapeutic; features; FOXP3

DESCRIPTION (provided by applicant): This confederation of projects is headed by Mark I. Greene who has been involved in the study of immune regulation and phenotype reversal for over 30 years. The goals of this highly integrated program project are to develop understanding of how the FoxpS proteins exert their biological effects and through this knowledge to develop translationally relevant therapeutics that disable or activate the Foxp3 complex. Although the theme of Foxp3 function resonates in each project, a variety of distinct technologies are actually employed to develop insights into how Foxp3 complexes operate and how to manipulate them, leading to a highly interactive group of experiments that should lead to therapeutics that will reach the clinic within the time frame of this program project. The long-term goals are reiterated in every project and all projects share recurrent themes of Treg phenotype manipulation. The studies to date have already lead to a rational therapeutic for autoimmune conditions that is entering a preliminary clinical trial at the NIH. The goal of Greene's project is to provide basic biochemical information of how the Foxp3 complex binds to chromatin in human cells. This information will be helpful in Andrew Wells's study of mouse chromatin - Foxp3 interactions and will be useful in the creation of transgenic and mutant mice that will help the Hancock project and the Wells project. Human and mouse Foxp3 complexes appear to have differences although both form large ensembles. The intent of Project 1 is to identify individual residues that are acetylated and phosphorylated and subdomains that mediate interactions with other repressive components. This information will provide a framework for Andrew Wells to examine chromatin remodeling events in the mouse and for Wayne Hancock to examine functional relevance in in vivo models. PROJECT 1: Foxp3 and immune regulation (Greene, M) PROJECT 1 DESCRIPTION (provided by applicant): Maintenance of unresponsiveness to self-antigens is essential for the prevention of autoimmunity but is an incompletely understood process. Our studies will focus on certain biochemical features of regulatory T cells (Treg) and how the Foxp3 complex mediates its repressive effects. While it is clear that mutations in human FOXP3 predispose individuals to human autoimmune conditions, it is unclear why the mutant protein fails to function as a transcriptional regulator. There is also limited detail of how FOXP3 itself interacts with the transcriptional machinery and which components of the FOXP3 ensembles exert phenotypic changes to render cells able to mediate suppression. Our proposed studies focus on the biochemistry of FOXP3 complexes, as well as in vivo models to examine modification of Treg function through rational biochemical alteration of the FOXP3 ensemble. The studies provide compelling evidence that a complex of specific histone acetyl transferases and histone deacetylases (HDAC) associate with FOXP3 to create a transcriptional represser. FOXP3 becomes acetylated and phosphorylated and is then able to mediate its activities. The essential areas of the grant focus on the signaling effects that lead to post translational changes and functions of the Foxp3 ensemble. A dominant theme that emerges is that Foxp3 is acted on by enzymes that modify its activity and stability and interactions with chromatin which lead to alterations in the actions of Treg in vitro and in vivo. A rational therapeutic emerges from these studies employing HDAC inhibitors to increase Treg acetylation modifications at specific lysine residues and thereby increase Treg function to ameliorate autoimmunity. The goal of Project 1 is to provide basic biochemical information of how the Foxp3 complex binds to chromatin in human cells. This information will be helpful in Andrew Wells's study of mouse chromatin- FoxpS interactions and will be useful in the creation of transgenic and mutant mice that will help the Hancock project and the Wells project. Human and mouse Foxp3 complexes appear to have differences. The intent of this project is to identify individual residues that are acetylated and phosphorylated and subdomains that mediate interactions with other repressive components. This information will provide a framework for Andrew Wells to examine chromatin remodeling events in the mouse and for Wayne Hancock to examine functional relevance in in vivo models.

项目描述（由申请人提供）：该联盟由Mark I. Greene领导，他从事免疫调节和表型逆转的研究超过30年。这个高度整合的项目的目标是了解FoxpS蛋白如何发挥其生物学作用，并通过这些知识开发与翻译相关的治疗方法，使Foxp3复合物失活或激活。虽然Foxp3功能的主题在每个项目中都有共鸣，但实际上，我们采用了各种不同的技术来深入了解Foxp3复合物的运作方式以及如何操纵它们，从而形成了一个高度互动的实验组，这些实验组应该会在这个项目的时间框架内产生治疗方法。每个项目都重申了长期目标，所有项目都有Treg表型操纵的反复主题。迄今为止的研究已经导致了一种合理的治疗自身免疫性疾病的方法，正在进入美国国立卫生研究院的初步临床试验。