NEW BETA CELL-SPECIFIC MEMBRANE PROTEIN RELEVANT TO IDDM

胰岛素依赖型糖尿病是一种常见的潜在致命性疾病。 每10,000名以下儿童中约有1人罹患这种疾病 每年在美国有20个。这种疾病的病因是一种 胰岛素分泌β细胞的绝对、不可逆转的丧失 胰岛，但是，破坏β的机制 细胞是未知的。许多证据表明，自身免疫力 是最有可能导致β细胞丢失的原因。最一致的 在这种青少年形式的糖尿病中发现的是 针对胰岛细胞的自身抗体。在过去的几年里 利用这些胰岛细胞抗体研究其发病机制 糖尿病，因为它们被认为与许多不同的自体- 结构和性质尚不完全清楚的抗原。更多- 此外，这些自身抗原性物质的功能也在很大程度上 未知。我们已经发现了一种可以结合到 大鼠β细胞上的相同抗原，大多数糖尿病儿童也 制造自身抗体来对抗。我们已经了解到，这些抗体与一种 仅在胰腺的β细胞中发现的膜蛋白。 蛋白质很大，分子量约为150,000。我们 已经能够从胰腺中分离出信使RNA，它可以 在体外合成这种蛋白质。我们建议利用 这种单抗和这种新型β细胞蛋白的发现 为了了解蛋白质及其基因的结构，探索 该蛋白可能的功能及其调控 在正常的β细胞中表达，以确定该蛋白是否 可能成为细胞介导的免疫系统手臂的靶子 它已被证明是导致β细胞死亡的原因 胰岛素依赖型糖尿病的动物模型，最后，确定 这种蛋白质的基因差异是否可能导致 糖尿病的遗传易感性。

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.