Targeting CD98 in Type 1 Diabetes

描述(申请人提供)：致病T细胞向胰腺的迁移，以及随后的激活和增殖，是I型糖尿病发病机制中的重要步骤。CD98是一种异源二聚体跨膜蛋白，参与氨基酸转运和整合素信号转导。在NOD小鼠模型中，整合素的表达和功能对自身免疫性糖尿病很重要，胰腺引流淋巴结中T细胞的增殖是疾病的标志。因此，我们已经开始研究CD98作为I型糖尿病的潜在靶点。我们的初步数据显示，以CD98为靶点的T细胞无法传播疾病，而控制T细胞的转移会导致β细胞破坏和明显的糖尿病。我们的总体假设是CD98控制糖尿病T细胞的迁移或增殖，因此是疾病干预的潜在靶点。本申请中提出的研究将探讨CD98缺失保护I型糖尿病的细胞和生化机制，并研究CD98靶向对正常免疫反应的潜在副作用。

DESCRIPTION (provided by applicant): The migration of pathogenic T cells to the pancreas, and their subsequent activation and proliferation, are important steps in the pathogenesis of type I diabetes. CD98 is a heterodimeric transmembrane protein that functions in amino acid transport and integrin signaling. Integrin expression and function are important for autoimmune diabetes in the NOD mouse model, and proliferation of T cells in pancreatic draining lymph nodes is a hallmark of disease. Therefore we have begun investigating CD98 as a potential target in type I diabetes. Our preliminary data shows that T cells in which CD98 has been targeted are unable to transfer disease, while transfer of control T cells causes beta cell destruction and overt diabetes. Our overall hypothesis is that CD98 controls migration or proliferation of diabetogenic T cells, and thus is a potential target for disease intervention. The research proposed in this application will Investigate the cellular and biochemical mechanisms by which CD98 deletion protects from type I diabetes, and to study potential side effects of CD98 targeting on normal immune responses.