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: 8829675
• 负责人: AVERIL I MA
• 金额: $ 33.6万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829675
• 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; Genetic study; 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而导致的，这些反应可能引发肠道炎症。树突状细胞（DC）是对微生物高度敏感的专门免疫细胞，可以有效激活炎症细胞。由于DC可能会经常或在语调上意识到肠中微生物的存在，因此它们引起炎症的倾向可能取决于其细胞内调节或与微生物相遇的“解释”。因此，调节由微生物触发的信号的细胞内蛋白可能对公开炎症反应的承诺至关重要。 A20是一种有效限制微生物传感途径的信号的酶，包括收费类受体（TLR），点头和TNF信号。因此，我们的中心假设是在DC中专门提供A20表达，可保留免疫稳态，并防止IBD和IBD相关关节炎。为了检验我们的中心假设，我们产生了一种新型小鼠A20FL/FL CD11C-CRE小鼠的菌株，其中A20专门从DC中删除。非常明显我们使用这些小鼠的初步数据表明，这些小鼠自发发展了结肠炎，血清阴性关节炎和脊椎关节炎，这是人类IBD中的刻板印象综合征。现在，我们建议使用这些A20FL/FL CD11-CRE小鼠来确定将DC中A20表达与这些挑衅性表型联系起来的细胞和分子机制。具体而言，我们将确定腔微生物和T细胞是否参与A20缺乏DC引起结肠炎和关节炎的病理生理（AIM 1）。由于A20可能会限制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受调节的信号是myD88依赖性的，并且哪些信号是myD88独立的。这些小鼠的研究将揭晓，细胞内直流信号和直流产物调节T细胞激活，结肠炎和血清阴性关节炎（AIM 2）。 A20是一种泛素化酶，可调节信号蛋白的泛素化，并与NFKB-1或ABIN-1的A20结合抑制剂结合。为了定义A20和Abin-1可以协作以限制DC中的信号的分子机制，我们还生成了DC中缺乏ABIN-1的小鼠。现在，我们将使用这些小鼠研究Abin-1与A20合作如何限制DC中的信号传导并预防结肠炎和关节炎（AIM 3）。