LVA CALCIUM CHANNEL AND PANCREATIC B CELL DEATH

描述（改编自申请人的摘要）：胰岛素依赖型糖尿病 mellitus (IDDM) 的特点是选择性破坏 B 细胞 朗格汉斯胰岛。 主要研究者的前任 研究表明，低压激活 (LVA) Ca2 通道可能是 参与细胞因子介导的 B 细胞死亡过程。 在这个 提案中，他将检验“LVA调节异常”的假设 钙通道通过细胞因子和其他因素改变 B 细胞钙 体内平衡，使这些细胞容易产生进一步的毒性，从而导致 B 细胞 胰岛炎期间的破坏。” 拟议研究的目的包括：1) 确定 LVA 钙通道在介导钙内流中的作用 和胰腺 B 细胞的凋亡。 LVA Ca2 通道拮抗剂 用于评估 LVA Ca2 通道在基础、葡萄糖和 去极化刺激 Ca2+ 流入。 LVA Ca2 通道的作用 时间和剂量依赖性 DNA 断裂和细胞死亡 细胞因子也将被研究。 2) 从一个克隆LVA通道 胰岛素分泌细胞系，INS-1。 通过使用RT-PCR方法，我们将推导出 LVA Ca2 的假定 α1 亚基的核苷酸序列 通道并在非洲爪蟾卵母细胞中表达。 3）研究机制 LVA 钙通道调节。 调查员将检查如何 细胞因子和性激素调节 LVA Ca2 通道的表达 糖尿病和非糖尿病动物模型。 这项研究将提供 对选择性 B 细胞发病机制的重要见解 人类 IDDM 中的破坏。

DESCRIPTION (Adapted from applicant's abstract): Insulin dependent diabetes mellitus (IDDM) is characterized by the selective destruction of B-cells of the pancreatic Islets of Langerhans. The principal investigator's previous studies suggest that a low-voltage-activated (LVA) Ca2+ channel may be involved in the process of cytokine-mediated B-cell death. In this proposal, he will test the hypothesis that "abnormal regulation of LVA calcium channels by cytokines and other factors changes B-cell calcium homeostasis, predisposing these cells to further toxicities causing B-cell destruction during insulitis." The aims of the proposed study include: 1) To identify the role of the LVA calcium channels in mediating calcium influx and apoptosis in pancreatic B-cells. LVA Ca2+ channel antagonists will be used to evaluate the role of LVA Ca2+ channels in basal, glucose- and depolarization-stimulated Ca2+ influx. The role of LVA Ca2+ channels in time- and dose-dependent DNA fragmentation and cell death induced by cytokines will also be investigated. 2) To clone the LVA channel from an insulin secreting cell line, INS-1. By using RT-PCR method, we will deduce the nucleotide sequence of the putative alpha1 subunit of the LVA Ca2+ channel and express it in Xenopus oocytes. 3) To investigate the mechanisms of LVA calcium channel regulation. The investigator will examine how cytokines and sex hormones regulate the expression of LVA Ca2+ channels in diabetic and non-diabetic animal models. This study will provide significant insight into the mechanisms of pathogenesis of selective B-cell destruction in human IDDM.