LVA CALCIUM CHANNEL AND PANCREATIC B CELL DEATH

LVA 钙通道和胰腺 B 细胞死亡

• 批准号: 2410082
• 负责人: MING LI
• 金额: $ 9.43万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-15 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2410082
• 关键词: NOD mouse; apoptosis; calcium channel; calcium flux; cell death; cytokine; cytotoxicity; gender difference; hormone regulation /control mechanism; inhibitor /antagonist; insulin; laboratory mouse; molecular cloning; pancreatic islets; receptor expression; sex hormones; tissue /cell culture; voltage gated channel

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.

描述(摘自申请者摘要)：胰岛素依赖型糖尿病 糖尿病(IDDM)的特征是选择性地破坏B细胞 朗格汉斯人的胰岛。首席调查员的前科 研究表明，低电压激活(LVA)的钙通道可能是 参与细胞因子介导的B细胞死亡过程。在这 建议，他将检验假设，即LVA的异常调节 细胞因子和其他因素引起的钙通道改变B细胞钙 动态平衡，使这些细胞容易产生进一步的毒性，导致B细胞 绝缘炎期间的破坏。“拟议研究的目的包括：1) LVA钙通道在钙内流调节中的作用 胰腺B细胞的凋亡。LVA钙通道拮抗剂将 用来评估LVA钙通道在基础、葡萄糖和 去极化刺激的钙离子内流。LVA钙通道在心肌梗死中的作用 辐射诱导的时间和剂量依赖的DNA断裂和细胞死亡 细胞因子也将被调查。2)克隆LVA通道的步骤 胰岛素分泌细胞系INS-1。通过使用RT-PCR方法，我们将推断 LVA钙离子α1亚基的核苷酸序列 在非洲爪哇的卵母细胞中引导和表达它。3)探讨其作用机制 LVA钙通道的调节。调查员将研究如何 细胞因子和性激素调节LVA钙通道的表达 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认识 对人类IDDM的破坏。