Immune chemistry and therapeutic features of FOXP3

描述(申请人提供)：这个项目联合会由Mark I.Greene领导，他参与免疫调节和表型逆转的研究已有30多年。这个高度整合的项目的目标是加深对FoxpS蛋白如何发挥其生物学效应的了解，并通过这些知识开发与翻译相关的疗法，使Foxp3复合体失活或激活。虽然Foxp3功能的主题在每个项目中都有共鸣，但实际上使用了各种不同的技术来深入了解Foxp3复合体是如何运作的，以及如何操纵它们，从而产生了一组高度互动的实验，这些实验应该会导致治疗学，并将在该计划项目的时间框架内到达临床。每个项目都重申了长期目标，所有项目都有Treg表型操纵这一反复出现的主题。到目前为止，这些研究已经导致了一种针对自身免疫性疾病的合理治疗方法，并正在进入NIH的初步临床试验。 格林项目的目标是提供有关Foxp3复合体如何与人类细胞中的染色质结合的基本生化信息。这些信息将有助于安德鲁·威尔斯对小鼠染色质-Foxp3相互作用的研究，并将有助于创造转基因和突变小鼠，这将有助于Hancock项目和Wells项目。人类和小鼠的Foxp3复合体似乎有差异，尽管它们都形成了巨大的整体。 项目1的目的是确定乙酰化和磷酸化的单个残基以及调节与其他抑制成分相互作用的亚结构域。这些信息将为安德鲁·威尔斯提供一个框架，以检查小鼠染色质重塑事件，并为韦恩·汉考克提供一个框架，以检查活体模型中的功能相关性。

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.