A20 Mediated Regulation of Colitis and Spondyloarthritis

A20 介导的结肠炎和脊柱关节炎调节

• 批准号: 8436190
• 负责人: AVERIL I MA
• 金额: $ 32.43万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8436190
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Binding; CD11 Antigens; Cell physiology; Cells; Colitis; Crohn' s disease; Data; Dendritic Cells; Enzymes; Functional disorder; Genes; Homeostasis; Human; Human Genetics; ITGAX gene; Immune; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Lead; Link; Mediating; Microbe; Molecular; Mouse Strains; Mus; Pathogenesis; Pathway interactions; Phenotype; Production; Protein Binding; Proteins; Public Health; Receptor Signaling; Regulation; Signal Transduction; Signaling Protein; Spondylarthritis; Syndrome; T cell differentiation; T-Cell Activation; T-Lymphocyte; TNF gene; Testing; Toll-like receptors; Ubiquitin; Ubiquitination; inhibitor/antagonist; microbial; mutant; novel; prevent; response; therapy development

DESCRIPTION (provided by applicant): Recent studies suggest that inflammatory bowel disease (IBD) results from the disruption of normal host immune cells responses to microbial molecules that can trigger inflammation in the intestine. Dendritic cells (DCs) are specialized immune cells that are highly sensitive to microbes and can potently activate inflammatory cells. As DCs may frequently or tonically sense the presence of microbes in the intestine, their propensity to cause inflammation may be dependent on their intracellular regulation or "interpretation" of encounters with microbes. Hence, intracellular proteins that regulate signals triggered by microbes may be central to the commitment to overt inflammatory responses. A20 is an enzyme that potently restricts signals from microbial sensing pathways, including Toll-like receptor (TLR), NOD and TNF signals. Thus, our central hypothesis is that A20 expression specifically in DCs preserves immune homeostasis and prevents IBD and IBD-associated arthritis. To test our central hypothesis, we have generated a novel strain of mice, A20FL/FL CD11c-Cre mice, in which A20 is deleted specifically from DCs. Remarkably; our preliminary data with these mice suggest that these mice spontaneously develop colitis, sero-negative arthritis and spondyloarthritis, a stereotypical syndrome in human IBD. We now propose to use these A20FL/FL CD11-cre mice to determine the cellular and molecular mechanisms linking A20 expression in DCs to these provocative phenotypes. Specifically, we will determine whether luminal microbes and T cells are involved in the pathophysiologies by which A20 deficient DCs cause colitis and arthritis (Aim 1). As A20 may restrict intracellular signals in DCs, including MyD88 dependent TLR signals, we will use compound A20FL/FL MyD88FL/FL CD11c-Cre mice to determine which A20 regulated signals in DCs are MyD88-dependent and which signals are MyD88-independent. Studies with these mice will unveil which intracellular DC signals and DC products regulate T cell activation, colitis, and sero-negative arthritis (Aim 2). A20 is a ubiquitn modifying enzyme that regulates ubiquitination of signaling proteins and also binds to A20 Binding Inhibitor of NFkB-1, or ABIN-1. To define the molecular mechanisms by which A20 and ABIN-1 may collaborate to restrict signals in DCs, we have also generated mice lacking ABIN-1 specifically in DCs. We will now use these mice to study how ABIN-1 collaborates with A20 to restrict signaling in DCs and prevent colitis and arthritis (Aim 3).

描述（由申请人提供）：最近的研究表明，炎症性肠病（IBD）是由于正常宿主免疫细胞对微生物分子的反应被破坏而引起的，而微生物分子会引发肠道炎症。树突状细胞 (DC) 是一种特殊的免疫细胞，对微生物高度敏感，可以有效激活炎症细胞。由于 DC 可能频繁地或紧张地感知肠道中微生物的存在，因此它们引起炎症的倾向可能取决于它们的细胞内调节或对与微生物相遇的“解释”。因此，调节微生物触发信号的细胞内蛋白可能是导致明显炎症反应的核心。 A20 是一种酶，可有效限制微生物传感途径的信号，包括 Toll 样受体 (TLR)、NOD 和 TNF 信号。因此，我们的中心假设是 A20 在 DC 中的特异表达可保持免疫稳态并预防 IBD 和 IBD 相关关节炎。为了检验我们的中心假设，我们培育了一种新的小鼠品系，即 A20FL/FL CD11c-Cre 小鼠，其中 A20 被从 DC 中特异性删除。值得注意的是；我们对这些小鼠的初步数据表明，这些小鼠自发地患上结肠炎、血清阴性关节炎和脊柱关节炎（人类 IBD 的一种典型综合征）。我们现在建议使用这些 A20FL/FL CD11-cre 小鼠来确定 DC 中 A20 表达与这些激发表型之间的细胞和分子机制。具体来说，我们将确定管腔微生物和 T 细胞是否参与 A20 缺陷 DC 引起结肠炎和关节炎的病理生理学（目标 1）。由于A20可能限制DC中的细胞内信号，包括MyD88依赖性TLR信号，我们将使用化合物A20FL/FL MyD88FL/FL CD11c-Cre小鼠来确定DC中哪些A20调节的信号是MyD88依赖性的，哪些信号是MyD88独立的。对这些小鼠的研究将揭示哪些细胞内 DC 信号和 DC 产物调节 T 细胞活化、结肠炎和血清阴性关节炎（目标 2）。 A20 是一种泛素修饰酶，可调节信号蛋白的泛素化，还可与 NFkB-1 或 ABIN-1 的 A20 结合抑制剂结合。为了确定 A20 和 ABIN-1 协同限制 DC 信号的分子机制，我们还培育了 DC 中特异性缺乏 ABIN-1 的小鼠。我们现在将使用这些小鼠来研究 ABIN-1 如何与 A20 合作来限制 DC 中的信号传导并预防结肠炎和关节炎（目标 3）。