The Function of Human AIM in Rheumatic Disease

人类 AIM 在风湿病中的作用

• 批准号: 6948562
• 负责人: DAVID R KARP
• 金额: $ 15.6万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-10 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6948562
• 关键词: T lymphocyte; apoptosis; chimeric proteins; clinical research; cytokine; dendritic cells; gene expression; human subject; immunocytochemistry; immunoregulation; inflammation; monoclonal antibody; monocyte; protein structure function; receptor expression; rheumatoid arthritis; synovial membrane; tissue /cell culture

DESCRIPTION (provided by applicant): Rheumatoid arthritis (IRA) is a chronic, inflammatory disorder affecting nearly 1% of the adult population. Despite effective therapies, it causes enormous physical disability and financial cost. Although autoimmune T and B lymphocytes are clearly part of the pathogenesis of RA, the innate immune system has become a focus of intense interest, in part due to the success of treatments that target cytokine products of Synovial macrophages and fibroblasts. Such therapies are not effective in all patients, however. Apoptosis Inhibitor expressed in Macrophages (AIM), a member of the Scavenger Receptor Cysteine Rich superfamily, has recently been shown to be a potent inducer of inflammatory cytokines in mouse macrophages and dendritic cells, in addition to its ability to block apoptosis in monocytic and lymphocytic cells. Human AIM is about 80% identical to mouse AIM, yet has distinct structural features. The objective of this exploratory/developmental project is to determine whether human AIM is also a potent stimulator of human cells, and can inhibit their apoptosis. Two specific aims will be investigated: 1. Determine the expression of human AIM protein by monocytic cells derived from tissue and peripheral blood 2. Determine the ability of human AIM to induce cytokine and inflammatory mediator release from human cells, and to inhibit apoptosis AIM will be quantified in serum from patients and controls, as well as in synovial fluid. AIM-expressing cells in RA synovial tissue will be characterized. Recombinant human AIM will be tested for its ability to stimulate moncytic cells from blood and synovial tissue to release inflammatory mediators, and to block apoptosis caused by Fas ligation or growth factor withdrawal. If successful, these studies will identify AIM as a novel target for therapies in autoimmune and inflammatory disease.

描述（由申请人提供）： 类风湿性关节炎 (IRA) 是一种慢性炎症性疾病，影响近 1% 的成年人。尽管治疗有效，但它会造成巨大的身体残疾和经济损失。尽管自身免疫性 T 和 B 淋巴细胞显然是 RA 发病机制的一部分，但先天免疫系统已成为人们强烈关注的焦点，部分原因是针对滑膜巨噬细胞和成纤维细胞细胞因子产物的治疗取得了成功。然而，此类疗法并非对所有患者都有效。巨噬细胞 (AIM) 中表达的细胞凋亡抑制剂 (AIM) 是清道夫受体富含半胱氨酸超家族的成员，最近已被证明除了能够阻止单核细胞和淋巴细胞细胞凋亡外，它还是小鼠巨噬细胞和树突状细胞中炎症细胞因子的有效诱导剂。人类 AIM 与小鼠 AIM 大约 80% 相同，但具有不同的结构特征。这个探索/开发项目的目的是确定人类 AIM 是否也是人类细胞的有效刺激剂，并可以抑制其凋亡。将研究两个具体目标： 1. 确定来自组织和外周血的单核细胞对人 AIM 蛋白的表达 2. 确定人 AIM 诱导人细胞释放细胞因子和炎症介质并抑制细胞凋亡的能力 将在患者和对照血清以及滑液中对 AIM 进行定量。将表征 RA 滑膜组织中表达 AIM 的细胞。将测试重组人 AIM 刺激血液和滑膜组织中的单胞细胞释放炎症介质以及阻止 Fas 连接或生长因子撤回引起的细胞凋亡的能力。如果成功，这些研究将确定 AIM 作为治疗自身免疫和炎症性疾病的新靶点。