Targeting CD98 in Type 1 Diabetes

1 型糖尿病中的靶向 CD98

• 批准号: 8594243
• 负责人: JOSEPH M CANTOR
• 金额: $ 15.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8594243
• 关键词: Adverse effects; Amino Acids; Antibody Formation; Autoimmune Diabetes; Autoimmune Process; B-Lymphocytes; Beta Cell; Biochemical; Cell physiology; Cells; Cities; Clonal Expansion; Cytotoxic T-Lymphocytes; Data; Development; Diabetes Mellitus; Disease; Experimental Diabetes Mellitus; Generations; Health; Immune; Immune response; Inbred NOD Mice; Inflammation; Insulin-Dependent Diabetes Mellitus; Integral Membrane Protein; Integrins; Intervention; Islets of Langerhans Transplantation; Lymphocyte; Lymphocyte Activation; Measures; Mediating; Mus; Pancreas; Pathogenesis; Recurrence; Research; Signal Transduction; T memory cell; T-Cell Proliferation; T-Lymphocyte; Testing; autoreactive T cell; islet; lymph nodes; migration; mouse model; mutant; pathogen; prevent; protein function; reconstitution

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. PUBLIC HEALTH RELEVANCE: Blocking the autoimmune attack mediated by lymphocytes in type I diabetes is a high priority, both to prevent the disease, and to stop its recurrence after islet cell transplant. We found that deleting CD98 on T lymphocyte immune cells makes them unable to cause experimental type I diabetes. We are proposing to investigate the mechanism of this protection, and to test what CD98 targeting might do to normal immune responses.

描述（由申请人提供）：致病性T细胞向胰腺的迁移及其随后的活化和增殖是I型糖尿病发病机制中的重要步骤。CD98是在氨基酸转运和整合素信号传导中起作用的异二聚体跨膜蛋白。在NOD小鼠模型中，整合素的表达和功能对于自身免疫性糖尿病是重要的，并且胰腺引流淋巴结中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，靶向CD98的T细胞不能转移疾病，而对照T细胞的转移导致β细胞破坏和明显的糖尿病。我们的总体假设是，CD98控制致糖尿病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调查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。 公共卫生相关性：阻断I型糖尿病中淋巴细胞介导的自身免疫攻击是一个高度优先事项，既可以预防疾病，也可以阻止胰岛细胞移植后的复发。我们发现，删除T淋巴细胞免疫细胞上的CD98使它们无法引起实验性I型糖尿病。我们建议研究这种保护的机制，并测试CD98靶向可能对正常免疫应答产生的影响。