Mechanisms of Viral-Induced Beta Cell Damage

描述（由申请人提供）：胰岛素依赖型糖尿病（IDDM）是一种自身免疫性疾病，其特征是朗格汉斯胰岛中发现的胰岛素分泌β细胞的选择性破坏。病毒感染被认为是该疾病发展过程中启动β细胞损伤的一个事件。虽然最近的研究已经开始揭示病毒感染调节淋巴细胞反应的机制，但很少有研究检测病毒感染对巨噬细胞活化的影响或病毒感染对β细胞功能和活力的直接影响。本研究的主要目标是阐明病毒感染调节巨噬细胞活化的生化机制，并确定病毒激活的途径导致β细胞功能和活力的丧失。利用一种在易感小鼠中诱导糖尿病的已知病毒，我们最近发现了三种调节巨噬细胞中炎症基因表达的新型抗病毒信号通路。在对病毒感染的反应中，β细胞的命运似乎取决于引发的反应，其中炎症反应似乎导致β细胞坏死，而在没有炎症的情况下，β细胞凋亡随之而来。有两个具体目标：1。验证PI3K激活状态决定巨噬细胞对病毒感染反应的假说。当PI3K处于激活状态时，病毒感染刺激IL-1、iNOS、COX-2等炎性基因的表达。当受到抑制时，病毒感染诱导巨噬细胞凋亡。2. 目的：阐明调控…反应的途径

DESCRIPTION (provided by applicant): Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that is characterized by selective destruction of insulin secreting beta-cells found in pancreatic islets of Langerhans. Viral infection is one event proposed to initiate beta-cell damage during the development of this disease. While recent studies have begun to unravel the mechanisms by which virus infection modulates the lymphocytic response, few studies have examined the impact of virus infection on macrophage activation or the direct effects of virus infection on beta-cell function and viability. The broad goals of this research are to elucidate the biochemical mechanisms by which virus infection regulates macrophage activation and to determine the virus-activated pathways that contribute to the loss of beta-cell function and viability. Using a virus known to induce diabetes in susceptible mice, we have recently identified three novel antiviral signaling pathways that regulate inflammatory gene expression in macrophages. In response to a virus infection, the fate of beta-cells appears to be dependent on the response elicited, where an inflammatory response appears to result in beta-cell necrosis, and in the absence of inflammation beta-cell apoptosis ensues. There are two specific aims: 1. To test the hypothesis that the activation state of PI3K determines the response of macrophages to virus infection. When PI3K is in an activated state, virus infection stimulates the expression of inflammatory genes such as IL-1, iNOS and COX-2. When inhibited, virus infection induces macrophage apoptosis. 2. To elucidate the pathways responsible for regulating the response of beta-cells to a virus infection. Specific experiments will determine the mechanisms by which virus infection stimulates inflammatory gene expression by beta-cells, and the pathways and determinants that are responsible for beta-cell death, either by necrosis or apoptosis. A number of biochemical, molecular, immunological, histochemical, and transgenic techniques will be utilized to investigate the cellular pathways through which viral infection stimulates macrophage activation and modulates beta-cell function and viability. It is hoped that insights into regulation of macrophage and beta-cell responses to virus infection gained from these proposed studies will influence the design of therapeutic strategies aimed at the prevention of this debilitating disease.