Role of chemokines in diabetes

趋化因子在糖尿病中的作用

• 批准号: 7781178
• 负责人: SERGIO A. LIRA
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781178
• 关键词: Ablation; Animal Model; Autoantigens; Autoimmune Diabetes; Blood Circulation; CCL2 gene; CCL21 gene; Cells; Development; Diabetes Mellitus; Disease; Family; Generations; Genetic; Graft Rejection; Hormones; Inbred NOD Mice; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Lead; Leukocytes; Lymphocyte; Lymphoid; Modeling; Pancreas; Pathogenesis; Pharmaceutical Preparations; Play; Process; Regulation; Role; Structure; Transgenic Organisms; Work; autoreactive T cell; chemokine; chemokine receptor; design; islet; lymph nodes; macrophage; migration; monocyte; novel; overexpression; prevent; public health relevance; receptor; sugar; trafficking

DESCRIPTION (provided by applicant): Recruitment of leukocytes into the pancreatic islets of Langerhans is a necessary step in the pathogenesis of Type I diabetes. Experimental evidence implicates chemokines in the regulation of leukocyte migration into the islets. Chemokines are expressed by islet cells in culture and within the pancreatic islets in animal models of diabetes. Moreover, as shown by our group and others, islet-specific transgenic expression of certain chemokines is sufficient to induce recruitment of lymphocytes and macrophages into the islets. Our recent work has shown that chemokines are critical for development of diabetes. We hypothesize that CCL2 and its receptor are critical for initial influx of monocytes and DC into the islets. This process can on itself lead to islet destruction if completely dysregulated. We hypothesize that the trafficking of DC carrying autoantigens produced during the initial inflammatory process into the peripancreactic lymph nodes is dependent on CCR7. We also hypothesize that trafficking of naove autoreactive T cells into the peripancreactic lymph nodes is dependent on CCR7. Together these processes may be critical for priming and expansion of autoreactive T cells. Finally, we hypothesize that reactivation of autoreactive T cells may happen within lymphoid-like structures generated by expression of CCL21 within the islets during the period preceding development of diabetes. In this proposal we will study the role of CCL2-CCR2 in the development of insulitis and diabetes and define the role of CCL21-CCR7 in the development of autoimmune diabetes. PUBLIC HEALTH RELEVANCE: Type I (or insulin-dependent) diabetes afflicts millions of people worldwide; one important component of the pathogenesis of this disease is the presence of inflammatory cells in the pancreas. The inflammatory cells eventually destroy cells producing insulin, a hormone that is important for the entry of sugars into cells - as the levels of insulin go down, the levels of sugar in the bloodstream increase, causing disease; we have identified factors that control the entry of inflammatory cells into the pancreas, suggesting that specific drugs may be designed to block such factors. We anticipate that blocking entry of inflammatory cells into the pancreas will prevent destruction of the insulin-producing cells; our work may thus prompt the generation of novel treatments for Type I diabetes.

描述（由申请人提供）：将白细胞募集到Langerhans的胰岛中是I型糖尿病发病机理的必要步骤。实验证据暗示着白细胞迁移到胰岛的调节中的趋化因子。趋化因子在培养物中和胰岛动物模型中的胰岛中的胰岛细胞表达。此外，如我们的小组和其他人所示，某些趋化因子的胰岛特异性转基因表达足以诱导淋巴细胞和巨噬细胞募集到胰岛中。我们最近的工作表明，趋化因子对于糖尿病的发展至关重要。我们假设CCL2及其受体对于单核细胞和DC初始涌入胰岛至关重要。如果完全失调，此过程本身可能会导致胰岛破坏。我们假设，在初始炎症过程中产生的携带自身抗原的直流运输到周围性淋巴结淋巴结取决于CCR7。我们还假设将NAOVE自动反应性T细胞运输到外周淋巴结中取决于CCR7。这些过程在一起对于自动反应性T细胞的启动和扩展可能至关重要。最后，我们假设自动反应性T细胞的重新激活可能发生在糖尿病发育之前的胰岛中CCL21在胰岛内的表达产生的类似淋巴样结构中发生。在此提案中，我们将研究CCL2-CCR2在胰岛炎和糖尿病发展中的作用，并定义CCL21-CCR7在自身免疫性糖尿病发展中的作用。 公共卫生相关性：I型（或胰岛素依赖性）糖尿病遭受了全球数百万人的困扰；该疾病发病机理的一个重要组成部分是胰腺中存在炎症细胞。炎症细胞最终破坏了产生胰岛素的细胞，这是一种激素，对于将糖进入细胞很重要 - 随着胰岛素的水平下降，血液中糖的水平升高，导致疾病；我们已经确定了控制炎症细胞进入胰腺的因素，这表明可以设计特定的药物来阻止此类因素。我们预计将炎症细胞进入胰腺会阻止胰岛素产生细胞的破坏。因此，我们的工作可能促使I型糖尿病的新型治疗方法产生。