Mechanisms of Viral-Induced Beta Cell Damage

描述(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，其特征是选择性破坏朗格汉斯胰岛中发现的分泌胰岛素的β细胞。在这种疾病的发展过程中，病毒感染被认为是启动β细胞损伤的一个事件。虽然最近的研究已经开始揭开病毒感染调节淋巴细胞反应的机制，但很少有研究研究病毒感染对巨噬细胞激活的影响，或者病毒感染对β细胞功能和活性的直接影响。这项研究的主要目标是阐明病毒感染调节巨噬细胞激活的生化机制，并确定导致β细胞功能和活性丧失的病毒激活途径。利用一种已知可在易感小鼠中诱发糖尿病的病毒，我们最近发现了三种新的抗病毒信号通路，它们调节巨噬细胞中炎症基因的表达。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，在没有炎症的情况下，β细胞随后发生凋亡。有两个特定的目的：1.验证PI3K的激活状态决定巨噬细胞对病毒感染的反应的假设。当PI3K处于激活状态时，病毒感染会刺激IL-1、iNOS和COX-2等炎症基因的表达。当被抑制时，病毒感染会诱导巨噬细胞凋亡。2.阐明调控反应的途径 β细胞对病毒感染的影响。具体的实验将确定病毒感染刺激β细胞炎症基因表达的机制，以及导致β细胞死亡的途径和决定因素，要么是通过坏死，要么是通过凋亡。许多生化、分子、免疫学、组织化学和转基因技术将被用于研究病毒感染刺激巨噬细胞激活和调节的细胞途径。 β细胞的功能和生存能力。希望从这些拟议的研究中获得的对巨噬细胞和β细胞对病毒感染反应的调控的见解将影响旨在预防这种衰弱疾病的治疗策略的设计。

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.