The Role of Rac in Mucosal Immune Regulation

描述（由申请人提供）：炎症性肠病（IBD）的确切发病机制尚不清楚。这个建议的目的是获得进一步了解肌动蛋白细胞骨架调节是如何参与控制粘膜免疫稳态。我们以前已经表明，Wiskott-Aldrich综合征蛋白（WASP），一种参与肌动蛋白细胞骨架重排的细胞内信号分子的缺乏，可导致人类和小鼠自发性结肠炎。这种结肠炎依赖于淋巴细胞的存在，并且可以通过转移WASP缺陷的T细胞来转移。Rac 1和Rac 2是小GTP酶的同种型，也控制肌动蛋白细胞骨架重排。与WASP缺陷小鼠一样，我们的初步数据表明缺乏Rac 2的动物也表现出调节性T细胞减少，最近发表的数据表明这些小鼠中枸橼酸诱导的结肠炎倾向增加，尽管我们在其他结肠炎模型中观察到保护作用。此外，最近的遗传分析表明Rac 1和Rac 2的单核苷酸多态性（SNP）与IBD风险之间存在关联。因此，肌动蛋白调节网络，特别是Rac 1和Rac 2，似乎在粘膜免疫中发挥作用。在这项提案中，我们的目标是进一步的Rac 1和/或Rac 2在调节和效应T细胞的产生，存活和迁移的作用，并确定是否缺陷是固有的T细胞或继发于先天免疫启动和教育。确定肌动蛋白调节如何控制粘膜T细胞生物学的机制可能有助于我们理解IBD的发病机制，并导致新的靶向治疗。 该提案的目标是建立在当前的初步数据基础上，为未来1-2年的R 01应用做准备，这将更多地关注肌动蛋白重排在分子水平上调节T细胞表型的方式以及维持粘膜稳态的先天免疫细胞-T细胞相互作用。更广泛的目标是为粘膜免疫学领域做出有意义的贡献，希望有一天能找到更有效，毒性更小的IBD治疗方法。

DESCRIPTION (provided by applicant): The precise pathogenesis of inflammatory bowel disease (IBD) is unknown. The aim of this proposal is to obtain further understanding of how actin cytoskeletal regulation is involved in controlling mucosal immune homeostasis. We have previously shown that deficiency of Wiskott-Aldrich Syndrome Protein (WASP), an intracellular signaling molecule involved in actin cytoskeletal rearrangements, can lead to spontaneous colitis in humans and mice. This colitis is dependent on the presence of lymphocytes and is transferrable by transferring WASP-deficient T cells. Rac1 and Rac2 are isoforms of small GTPases that also control actin cytoskeletal rearrangements. Like WASP-deficient mice, our preliminary data suggest animals lacking Rac2 also demonstrated decreased regulatory T cells, and recent published data suggest increased propensity for Citrobacter-induced colitis in these mice, although we observe protection in other models of colitis. In addition, recent genetic analyses have demonstrated an association between single nucleotide polymorphisms (SNPs) in Rac1 and Rac2 and IBD risk. Therefore, the actin regulatory network, particularly Rac1 and Rac2, appears to play a role in mucosal immunity. In this proposal, we aim to further character the role of Rac1 and/or Rac2 in regulatory and effector T-cell generation, survival, and migration and determine whether defects are intrinsic to the T cells or secondary to innate immune priming and education. Determining the mechanisms underlying how actin regulation controls mucosal T cell biology may aid in our understanding of the pathogenesis of IBD and lead to new targeted therapies. The goal of this proposal is to build upon current preliminary data in preparation for an R01 application in the coming 1-2 years, which will focus more on the manner in which actin rearrangements may function to regulate T-cell phenotype at a molecular level and innate immune cell-T cell interactions that maintain mucosal homeostasis. The broader aim is to make a meaningful contribution to the field of mucosal immunology in the hope of someday finding more effective and less toxic treatments for IBD.