Deciphering How Aberrant Innate Immune Cells Induce Colitis

破译异常的先天免疫细胞如何诱发结肠炎

• 批准号: 7797525
• 负责人: Deanna D Nguyen
• 金额: $ 15.82万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797525
• 关键词: Actins; Adverse effects; Animal Model; Antigen Presentation; Basic Science; CD4 Positive T Lymphocytes; Caring; Cells; Chemotaxis; Clinical; Colitis; DNA Sequence Rearrangement; Data; Defect; Dendritic Cells; Development; Disease; Goals; Hematopoietic; Human; Immune; Immunology; Inflammation; Inflammatory Bowel Diseases; Knockout Mice; Lead; Lymphocyte; Mediating; Modeling; Mus; Onset of illness; Pathogenesis; Patients; Population; Proteins; Research; Research Personnel; Role; Signaling Molecule; T-Lymphocyte; T-Lymphocyte Subsets; Thinking; Time; Wiskott-Aldrich Syndrome; Work; Writing; base; career; cell type; experience; human disease; knowledge base; novel; public health relevance; skills

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.

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。该提案的目的是通过仔细检查IBD的新型动物模型Wiskott-Aldrich综合征蛋白（WASP）敲除（KO）小鼠的发病机制来进一步了解这种人类疾病。WASP是Wiskott-Aldrich综合征（WAS）患者中的蛋白质缺陷，是一种仅在造血细胞中表达的细胞内信号分子，并参与肌动蛋白细胞骨架重排。在WKO小鼠和WAS患者中已经描述了许多免疫细胞亚群的缺陷，包括活化、抑制功能、趋化性、抗原呈递和足体形成。最值得注意的是，WASP KO小鼠发生结肠炎，类似于10%患有IBD样结肠炎的WAS患者。初步研究表明，需要淋巴细胞和CD 4 + T细胞足以转移疾病。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细胞转化为大肠杆菌细胞。在这项提议中，我们的目标是确定先天免疫细胞，特别是DC，在WKO小鼠结肠炎发展中的作用，并确定它们可能具有哪些内在缺陷，以及它们如何与不同的T细胞亚群异常相互作用，导致结肠炎的发展。确定该模型中疾病发作的细胞类型和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。我希望，未来五年的工作成果将为我的发现奠定基础，从而产生一系列有意义和深刻的问题，使我能够成为一名独立的研究者。我计划从事一项学术事业，将IBD患者护理方面的兼职临床工作与我在粘膜免疫学领域的基础科学研究上花费的大部分时间相结合。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。 公共卫生相关性：研究缺乏Wiskott-Aldrich综合征蛋白（Wiskott-Aldrich综合征患者中缺失的分子）的小鼠的结肠炎症，将有助于更好地了解人类炎症性肠病（IBD）的发病机制。破译特定的异常细胞群体和介导其不良反应的因素将有望导致IBD的新疗法。