Deciphering How Aberrant Innate Immune Cells Induce Colitis

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。这项建议的目的是通过仔细研究一种新的IBD动物模型-Wiskott-Aldrich综合征蛋白(WASP)基因敲除(KO)小鼠的发病机制，进一步了解这种人类疾病。Wiskott-Aldrich综合征(Wiskott-Aldrich综合征)患者的缺陷蛋白WASP是一种细胞内信号分子，仅在造血细胞中表达，并参与肌动蛋白的细胞骨架重排。在WKO小鼠和AS患者中已经描述了许多免疫细胞亚群的缺陷，包括激活、抑制功能、趋化、抗原提呈和足体形成。最值得注意的是，WASP KO小鼠患上结肠炎，类似于10%患有IBD样结肠炎的患者。初步研究表明，淋巴细胞是必需的，而CD4+T细胞足以传播疾病。最近的数据表明，WKO先天免疫细胞，潜在的树突状细胞(DC)，可以将正常的T细胞转化为结肠癌细胞。在这项建议中，我们旨在确定先天免疫细胞，特别是树突状细胞，在WKO小鼠结肠炎发展中的作用，并确定它们可能存在哪些固有缺陷，以及它们可能如何与不同的T细胞亚群异常相互作用而导致结肠炎发展。在这个模型中确定细胞类型和发病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。未来几年的目标是建立我的知识基础、研究技能和独立思考和科学写作的经验。希望未来五年的工作结果将产生一个发现的基础，导致一系列有意义和深刻的问题，使我能够成为一名独立的调查员。我计划从事一项学术生涯，将护理IBD患者的兼职临床工作与我大部分时间用于粘膜免疫学领域的基础科学研究相结合。更广泛的目标是为黏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、毒性更低的IBD治疗方法。 公共卫生相关性：研究缺乏Wiskott-Aldrich综合征蛋白的小鼠的结肠炎症，Wiskott-Aldrich综合征患者中缺失的一种分子，将有助于更好地理解人类炎症性肠病(IBD)的发病机制。破译特定的异常细胞群体及其不良影响的因素将有望导致IBD的新疗法。

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 this human disease by closely examining the pathogenesis of a novel animal model of IBD, the Wiskott-Aldrich Syndrome Protein (WASP) knockout (KO) mice. WASP, the protein defective in patients with Wiskott-Aldrich Syndrome (WAS), is an intracellular signaling molecule expressed exclusively in hematopoietic cells and is involved in actin cytoskeletal rearrangements. Defects in many immune cell subsets have been described in WKO mice and WAS patients, including activation, suppressive function, chemotaxis, antigen presentation, and podosome formation. Most notably, WASP KO mice develop colitis, similar to 10% of WAS patients who suffer from an IBD-like colitis. Preliminary studies have shown that lymphocytes are required and CD4+ T cells are sufficient to transfer disease. More recent data suggest that WKO innate immune cells, potentially dendritic cells (DCs), can convert normal T cells into colitogenic cells. In this proposal, we aim to determine the role of innate immune cells, specifically DCs, in colitis development in WKO mice and to determine what intrinsic defects they may have and how they may aberrantly interact with different T cell subsets to lead to colitis development. Determining the cell types and mechanisms underlying disease onset in this model may aid in our understanding of the pathogenesis of IBD and lead to new targeted therapies. The goal of these next few years is to build my knowledge base, research skills, and experience with independent thinking and scientific writing. The hope is that the result of these next five years of work will yield a basis of discovery leading to a meaningful and profound set of questions that will allow me to become an independent investigator. I plan to pursue an academic career that combines part-time clinical work in the care of IBD patients with the majority of my time spent on basic science research in the field of mucosal immunology. 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. PUBLIC HEALTH RELEVANCE: Studying the colonic inflammation in mice lacking the Wiskott-Aldrich Syndrome protein, a molecule missing in patients with Wiskott-Aldrich Syndrome, will lead to better understanding of the mechanisms underlying pathogenesis of inflammatory bowel disease (IBD) in humans. Deciphering the specific abnormal cellular population and the factors that mediate their adverse effects will hopefully lead to novel therapies for IBD.