NEW BETA CELL-SPECIFIC MEMBRANE PROTEIN RELEVANT TO IDDM

与 IDDM 相关的新 Beta 细胞特异性膜蛋白

• 批准号: 3245073
• 负责人: ROBERT C MCEVOY
• 金额: $ 20.07万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3245073
• 关键词: affinity chromatography; autoantibody; autoantigens; cellular immunity; diabetes mellitus genetics; embryo /fetus protein; embryo /fetus tissue /cell culture; genetic library; genetic polymorphism; genetic regulation; growth /development; human tissue; immunocytochemistry; immunoprecipitation; insulin dependent diabetes mellitus; intracellular transport; laboratory mouse; laboratory rat; membrane proteins; molecular cloning; monoclonal antibody; northern blottings; nucleic acid probes; pancreatic islets; posttranslational modifications; protein biosynthesis; protein purification; protein structure function; restriction mapping; southern blotting; tissue /cell culture; transfection; western blottings

Insulin-dependent diabetes mellitus is a common, potentially lethal disease that strikes approximately 1 in 10,000 children under the age of 20 in the United States each year. The cause of this disease is an absolute, irreversible loss of the insulin-producing beta cells of the pancreatic islets, but, the mechanism of the destruction of the beta cells is unknown. Many lines of evidence have pointed to autoimmunity as the most likely cause of the beta cell loss. The most consistent finding in this juvenile form of diabetes is the presence of autoantibodies against the islet cells. There has been difficulty in taking advantage of these islet cell antibodies to study the mechanism of diabetes as they are believed to bind to a number of different auto- antigens whose structure and properties are incompletely known. More- over, the functions of these autoantigenic substances are also largely unknown. We have discovered a mouse monoclonal antibody that binds to the same antigen on rat beta cells that most children with diabetes also make autoantibodies to. We have learned that these antibodies bind to a membrane protein that is found only in the beta cells of the pancreas. Protein is large with a molecular weight of approximately 150,000. We have also been able to isolate messenger RNA from the pancreas which can synthesize this protein in vitro. We propose to take advantage of the discovery of this monoclonal antibody and this novel beta cell protein to understand the structure of the protein and its gene, to explore the possible functional roles for the protein and the regulation of its expression in the normal beta cell, to determine whether this protein might serve as a target for the cell-mediated arm of the immune system which has been shown to be responible for beta cell killing in the animal models of insulin-dependent diabetes, and, lastly, to ascertain whether differences in the gene for this protein may contribute to the genetic susceptibility for diabetes.

胰岛素依赖型糖尿病是一种常见的， 这种疾病在10，000岁以下的儿童中约占1 美国每年20。 这种疾病的原因是 绝对的，不可逆的损失的胰岛素产生β细胞的 胰岛，但是，破坏β细胞的机制 细胞未知。 许多证据都指向自身免疫 最有可能导致β细胞丧失 最一致的 在这种青少年糖尿病中发现的是 针对胰岛细胞的自身抗体 一直以来， 利用这些胰岛细胞抗体研究其机制 糖尿病，因为他们被认为是结合到一些不同的汽车， 其结构和性质尚不完全清楚的抗原。 更多- 此外，这些自身抗原物质的功能也在很大程度上 未知 我们发现了一种小鼠单克隆抗体， 老鼠β细胞上的抗原与大多数糖尿病儿童的抗原相同， 产生自身抗体 我们已经了解到这些抗体与一种 仅在胰腺β细胞中发现的膜蛋白。 蛋白质很大，分子量约为150，000。 我们 也能够从胰腺中分离出信使RNA， 在体外合成这种蛋白质。 我们建议利用 这种单克隆抗体和这种新型β细胞蛋白的发现 了解蛋白质及其基因的结构，探索 可能的功能作用的蛋白质和调节其 在正常β细胞中的表达，以确定这种蛋白质是否 可能作为免疫系统细胞介导的一个靶点 它被证明是负责β细胞杀伤在 胰岛素依赖型糖尿病的动物模型，最后，为了确定 这种蛋白质的基因差异是否有助于 糖尿病的遗传易感性