The role of FAST in immune-mediated inflammatory disease

FAST 在免疫介导的炎症性疾病中的作用

• 批准号: 6814060
• 负责人: PAUL J. ANDERSON
• 金额: $ 36.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6814060
• 关键词: SDS polyacrylamide gel electrophoresis; binding sites; biological signal transduction; biotechnology; clinical research; genetically modified animals; human subject; immunity; inflammation; intracellular transport; laboratory mouse; laboratory rabbit; macrophage inflammatory proteins; pathologic process; phosphoproteins; posttranslational modifications; prostaglandin endoperoxide synthase; protein protein interaction; protein structure function; rheumatoid arthritis; serine; site directed mutagenesis; systemic lupus erythematosus; threonine; tumor necrosis factor alpha; western blottings

DESCRIPTION (provided by applicant): The objective of this proposal is to determine the role of FAST (Fas-activated serine/threonine phosphoprotein) in the pathogenesis of immune-mediated inflammatory disease. FAST is overexpressed in peripheral blood cells derived from patients with rheumatoid arthritis and systemic lupus erythematosus. FAST binds to TIA-1, an adenine/uridine-rich element (ARE)-binding protein that inhibits the translation of select pro-inflammatory proteins, including TNF, IL-1, COX-2 and MMP-13. We show that FAST can inhibit TIA-1 mediated translational silencing. FAST also inhibits Fas-induced apoptosis, probably by inhibiting TIA-1 mediated translational silencing of ARE-containing transcripts encoding inhibitors of apoptosis. We hypothesize that FAST contributes to the pathogenesis of immune-mediated inflammatory disease by promoting the expression of pro-inflammatory proteins and inhibiting Fas-induced apoptosis. The specific aims are: 1) To complete a structure:function analysis of the FAST:TIA-1 complex, 2) To determine the effect of FAST on the expression of pro-inflammatory proteins, 3) To determine how FAST regulates apoptosis, and 4) To determine whether FAST modulates immune-mediated inflammatory disease in transgenic mice. We will determine whether FAST promotes the expression of pro-inflammatory proteins in macrophages. We will identify FAST mutants that cannot bind to TIA-1 to determine whether TIA-1 is essential for this function. We will identify the mRNAs encoding inhibitors of apoptosis that are targeted by FAST to inhibit Fas-induced apoptosis. We will determine how interactions with TIA-1 and BCL-XL regulate the function of FAST. Finally, we will generate transgenic mice that overexpress FAST and mutant mice that lack FAST to determine its importance in the initiation and/or propagation of immune-mediated inflammatory disease.

描述（由申请人提供）： 该提案的目的是确定快速（FAS激活的丝氨酸/苏氨酸磷蛋白）在免疫介导的炎性疾病发病机理中的作用。 FAST在来自类风湿关节炎和全身性红斑狼疮患者的外周血细胞中过表达。快速结合TIA-1，TIA-1是一种富含腺嘌呤/尿苷元素（IS）结合蛋白，可抑制精选促炎蛋白的翻译，包括TNF，IL-1，COX-2和MMP-13。我们表明，快速可以抑制TIA-1介导的翻译沉默。快速还可以抑制FAS诱导的凋亡，这可能是通过抑制TIA-1介导的含有凋亡抑制剂的含有含有的转录本的翻译沉默。我们假设快速通过促进促炎蛋白的表达并抑制FAS诱导的凋亡，从而有助于免疫介导的炎症性疾病的发病机理。具体目的是：1）完成结构：快速的功能分析：TIA-1复合物，2）确定快速对促炎蛋白表达的影响，3）确定如何调节凋亡的速度和4）确定快速调节转基因小鼠中免疫介导的炎症性疾病。我们将确定快速促进巨噬细胞中促炎蛋白的表达。我们将确定无法与TIA-1结合的快速突变体，以确定TIA-1对于此功能是否必不可少。我们将鉴定出编码凋亡抑制剂的mRNA，这些mRNA被FAST抑制FAS诱导的细胞凋亡。我们将确定与TIA-1和BCL-XL的相互作用如何调节快速的功能。最后，我们将产生过表达快速和突变小鼠的转基因小鼠，这些小鼠无法快速地确定其在免疫介导的炎症性疾病的启动和/或传播中的重要性。