Rho GTPase-mediated pathways in autoimmune arthritis

Rho GTPase 介导的自身免疫性关节炎通路

• 批准号: 8770006
• 负责人: ALESSANDRA B PERNIS
• 金额: $ 43.88万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8770006
• 关键词: Adverse effects; Arthritis; Autoantigens; Autoimmune Responses; Autoimmunity; Binding; Binding Proteins; Biological; Biology; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cell Nucleus; Cells; Clinical Trials; Clone Cells; Development; Disease; Effectiveness; Event; Exhibits; Genes; Goals; Guanine Nucleotide Exchange Factors; IRF4 gene; Immune response; Interleukin-17; Kidney Diseases; Knowledge; Mediating; Modeling; Molecular; Mus; Names; Pathway interactions; Phosphorylation; Play; Production; Protein Isoforms; Proteins; Reporting; Rho-associated kinase; Role; Signal Pathway; Signal Transduction; Syndrome; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic; Transgenic Organisms; Translating; Treatment Efficacy; Treatment Protocols; autoimmune arthritis; cytokine; fasudil; genetic approach; inhibitor/antagonist; lupus-like; novel; novel strategies; novel therapeutics; prevent; promoter; response; rho GTP-Binding Proteins; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Rho GTPases (which include Rac and RhoA) are molecular switches that play a fundamental role in biology due to their ability to regulate both cytoskeletal dynamics and signaling pathways. Rac and RhoA target different effectors and thus regulate distinct signaling events. Rac and RhoA also cross-regulate each other since activated Rac inhibits RhoA activity and vice versa. One of the major effectors of RhoA is the Rho kinases (or ROCKs). Activation of Rho GTPases plays a key role in immune responses. Guanine nucleotide exchange factors (GEFs) are the major proteins regulating the activation of Rho GTPases. In the course of isolating proteins interacting with IRF4, a transcription factor required for the differentiation of TH-17 cells, we cloned a novel GEF that we termed IBP (IRF-4 Binding Protein), also known as Def6. Since Def6 is the official name of the gene, IBP will be hereafter referred to as Def6. Def6 is highly expressed in T cells, and, upon TCR engagement, activates Rac but not RhoA. Def6 can also be found in the nucleus where it interacts with IRF4. We previously reported that Def6-deficient mice spontaneously develop a lupus-like syndrome. We have recently found that TCR transgenic (DO11.10) Def6-deficient mice spontaneously develop RA-like arthritis. The autoimmune responses in these mice are due to an aberrant ability of CD4+ T cells to produce IL-17 and IL-21 in response to self-antigens. At a molecular level, Def6-deficient T cells exhibit defective Rac activation and an enhanced ability of IRF4 to bind to the IL-17 and IL-21 promoters. Consistent with the notion that Rac activation inhibits RhoA- induced pathways, we have recently observed that the absence of Def6 also leads to increased ROCK2 activity. Importantly, we have found that ROCK2 phosphorylates IRF4 and regulates its ability to control the production of IL-17 and IL-21. In line with these findings, Fasudil, a ROCK inhibitor, blocked the aberrant IL-17 and IL-21 production detected in the absence of Def6 and prevented development of arthritis in Def6-deficient DO11.10 mice. We now propose that the Def6-ROCK2-IRF4 axis regulates the production of IL-17 and IL-21 and that ROCK inhibitors represent a novel approach for the treatment of autoimmune arthritis. The specific goals of this proposal are: 1) To investigate the interplay between Def6 and ROCK2, 2) to delineate the role of T-cell ROCK2 in autoimmune arthritis and 3) to broadly assess the effectiveness of ROCK inhibitors in autoimmune arthritis.

描述（由申请人提供）：Rho GTP酶（包括Rac和RhoA）是分子开关，由于其调节细胞骨架动力学和信号传导途径的能力，在生物学中发挥重要作用。Rac和RhoA靶向不同的效应物，从而调节不同的信号传导事件。Rac和RhoA也相互交叉调节，因为活化的Rac抑制RhoA活性，反之亦然。RhoA的主要效应物之一是Rho激酶（或ROCK）。Rho GTP酶的激活在免疫应答中起关键作用。鸟嘌呤核苷酸交换因子（GEFs）是调节Rho GTP酶活化的主要蛋白质。在分离与TH-17细胞分化所需的转录因子IRF-4相互作用的蛋白质的过程中，我们克隆了一种新的GEF，我们称之为IBP（IRF-4结合蛋白），也称为Def6。由于Def6是该基因的正式名称，因此IBP将在下文中被称为Def6。Def6在T细胞中高度表达，并且在TCR接合时激活Rac而不是RhoA。Def6也可以在细胞核中发现，在那里它与IRF4相互作用。我们以前报道，Def6缺陷小鼠自发发展狼疮样综合征。我们最近发现TCR转基因（DO11.10）Def6缺陷小鼠自发地发展RA样关节炎。这些小鼠中的自身免疫应答是由于CD4 + T细胞响应于自身抗原产生IL-17和IL-21的异常能力。在分子水平上，Def6缺陷型T细胞表现出缺陷的Rac激活和IRF4结合IL-17和IL-21启动子的能力增强。与Rac激活抑制RhoA诱导的途径的观点一致，我们最近观察到Def6的缺乏也导致ROCK 2活性增加。重要的是，我们发现ROCK 2磷酸化IRF 4并调节其控制IL-17和IL-21产生的能力。与这些发现一致，法舒地尔（一种ROCK抑制剂）阻断了在缺乏Def6的情况下检测到的异常IL-17和IL-21产生，并预防了Def6缺陷型DO11.10小鼠中关节炎的发生。我们现在提出Def6-ROCK 2-IRF4轴调节IL-17和IL-21的产生，并且ROCK抑制剂代表了治疗自身免疫性关节炎的新方法。该提案的具体目标是：1）研究Def6和ROCK 2之间的相互作用，2）描述T细胞ROCK 2在自身免疫性关节炎中的作用，3）广泛评估ROCK抑制剂在自身免疫性关节炎中的有效性。