Role of defective clearance of apoptotic beta-cell in pathogenesis of T1D

凋亡 β 细胞清除缺陷在 T1D 发病机制中的作用

• 批准号: 7313900
• 负责人: ZHONGMIN ALEX MA
• 金额: $ 25.43万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7313900
• 关键词: Adolescent; Age; Antibodies; Apoptosis; Apoptotic; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Beta Cell; Biological Assay; Cell Death; Cells; Cessation of life; Chemotactic Factors; Chemotaxis; Complex; Defect; Dendritic Cells; Development; Diabetes Mellitus; Down-Regulation; Eating; Epitopes; Event; Failure; Figs - dietary; Goals; Human; In Vitro; Inbred NOD Mice; Individual; Inflammation; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Lentivirus Vector; Light; Link; Lysophosphatidylcholines; Mediating; Mus; Neonatal; Pancreas; Pathogenesis; Patients; Phagocytes; Phospholipase A2; Physiological; Play; Principal Investigator; Proteins; Rattus; Recruitment Activity; Reporting; Rodent; Role; Signal Transduction; Small Interfering RNA; Specialist; Structure of beta Cell of islet; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic; Thinking; Week; cell killing; concept; disability; gene therapy; immunogenic; inhibitor/antagonist; islet; killings; macrophage; monocyte; mouse model; novel; prevent; programs; uptake; vector

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an autoimmune disease resulting from a selective destruction of the pancreatic beta-cells. The etiologic steps leading to T1D are complex, unclear, and controversial. Our long-term goal is to elucidate the mechanisms by which beta-cell specific autoantigens are made available in the genetically susceptible individuals to trigger the autoimmunity. Apoptosis is a programmed and physiological form of cell death. The ultimate objective of apoptotic program is to remove apoptotic cells to prevent release of their components. Failure to do so promptly has serious consequences for inflammation and autoimmunity. Recent studies have implicated apoptotic cells as being potential reservoirs of autoantigens that might initiate and drive systemic autoimmunity in susceptible hosts. It has been shown that physiological beta-cell death triggers priming of self-reactive T cells by dendritic cells (DCs) in autoimmune NOD mice. The uptake of dying cells by DCs in NOD mice came as a surprise because macrophages are thought to be the specialists in clearing apoptotic cellular debris, suggesting the impaired clearance of dying beta-cells in NOD mice. In light of these observations, we hypothesize that failure to release "find-me" signals or to present the "eat-me" signals by beta-cells undergoing developmental apoptosis in juvenile NOD mice or susceptible humans results in defective clearance of apoptotic beta-cells, which subsequently results in release of immunogenic intracellular components triggering autoimmunity. Ca2+independent PLA2 (iPLA2) is key player in generating lysophosphatidylcholine (LPC) as a "find-me" signal by apoptotic cells to attract phagocytes. The goal of this study is to test a novel hypothesis that failure to produce "find-me" signal LPC by iPLA2 leads to the defective clearance of apoptotic beta-cells, which makes beta-cell specific autoantigens available predisposing to T1D in the susceptible individuals. The specific aims are to: 1) test the hypothesis that iPLA2 plays an important role for apoptotic beta-cells to release chemotactic factor LPC to recruit macrophages and 2) test the hypothesis that the decreased level of iPLA2 in NOD mice leads to failure to clear apoptotic beta-cells, which makes beta- cell specific autoantigens available. By conducting this study, we will be able to elucidate the critical events that activate and promote T cell invasion of the islets to specifically kill beta-cell and to develop therapeutic strategy preventing the initiation of autoimmunity in T1D. By conducting this study, we will be able to elucidate the critical events that activate and promote T cell invasion of the islets to specifically kill beta-cell and to develop therapeutic strategy preventing the initiation of autoimmunity in T1D.

描述（由申请人提供）：1型糖尿病（T1 D）是一种自身免疫性疾病，由胰腺β细胞的选择性破坏引起。导致T1 D的病因学步骤是复杂的、不清楚的和有争议的。我们的长期目标是阐明β细胞特异性自身抗原在遗传易感个体中可用于触发自身免疫的机制。细胞凋亡是细胞死亡的一种程序性和生理性形式。凋亡程序的最终目的是去除凋亡细胞以防止其组分的释放。如果不及时这样做，会对炎症和自身免疫产生严重后果。最近的研究表明，凋亡细胞是潜在的自身抗原库，可能会引发和驱动易感宿主的全身性自身免疫。已经表明，生理性β细胞死亡触发自身免疫NOD小鼠中树突状细胞（DC）对自身反应性T细胞的致敏。NOD小鼠中DC对垂死细胞的摄取令人惊讶，因为巨噬细胞被认为是清除凋亡细胞碎片的专家，这表明NOD小鼠中垂死β细胞的清除受损。根据这些观察结果，我们假设在幼年NOD小鼠或易感人群中经历发育性凋亡的β细胞未能释放“发现我”信号或呈递“吃我”信号导致凋亡β细胞的清除缺陷，这随后导致释放免疫原性细胞内组分触发自身免疫。Ca 2+非依赖性PLA 2（iPLA 2）是通过凋亡细胞产生溶血磷脂酰胆碱（LPC）作为“找到我”信号以吸引吞噬细胞的关键参与者。本研究的目的是测试一种新的假设，即iPLA 2未能产生“find-me”信号LPC导致凋亡β细胞的清除缺陷，这使得β细胞特异性自身抗原可用于易感个体中的T1 D。具体目标是：1）检验iPLA 2对凋亡β细胞释放趋化因子LPC以募集巨噬细胞起重要作用的假设，和2）检验NOD小鼠中iPLA 2水平降低导致不能清除凋亡β细胞的假设，这使得β细胞特异性自身抗原可用。通过进行这项研究，我们将能够阐明激活和促进T细胞侵入胰岛以特异性杀死β细胞的关键事件，并开发预防T1 D中自身免疫启动的治疗策略。通过进行这项研究，我们将能够阐明激活和促进T细胞侵入胰岛以特异性杀死β细胞的关键事件，并开发预防T1 D中自身免疫启动的治疗策略。