Immune chemistry and therapeutic features of FOXP3

描述（由申请人提供）：这个项目联盟是由马克一。格林博士从事免疫调节和表型逆转研究30多年。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出禁用或激活Foxp 3复合物的预防相关疗法。虽然Foxp 3功能的主题在每个项目中都有共鸣，但实际上采用了各种不同的技术来深入了解Foxp 3复合物如何运作以及如何操纵它们，从而形成了一组高度互动的实验，这些实验应该会导致在该项目的时间范围内到达临床的治疗方法。长期目标在每个项目中重申，所有项目都有Treg表型操纵的重复主题。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，该方法正在NIH进行初步临床试验。 格林项目的目标是提供Foxp 3复合物如何与人类细胞染色质结合的基本生物化学信息。这些信息将有助于安德鲁威尔斯的研究小鼠染色质-Foxp 3相互作用，并将有助于创造转基因和突变小鼠，这将有助于汉考克项目和威尔斯项目。人类和小鼠Foxp 3复合物似乎存在差异，尽管两者都形成大的集合体。 项目1的目的是鉴定乙酰化和磷酸化的单个残基以及介导与其他抑制组分相互作用的亚结构域。这些信息将为Andrew威尔斯提供一个框架，以检查小鼠中的染色质重塑事件，并为韦恩汉考克检查体内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.