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LVA CALCIUM CHANNEL AND PANCREATIC B CELL DEATH

LVA 钙通道和胰腺 B 细胞死亡

基本信息

批准号：
6381008
负责人：
MING LI
金额：
$ 11.22万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-15 至 2003-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6381008
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

项目摘要

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（改编自申请人摘要）：胰岛素依赖型糖尿病胰岛素依赖型糖尿病（IDDM）的特征是选择性破坏B细胞，胰岛首席研究员之前研究表明，低电压激活（LVA）的钙通道可能是参与甜菜碱介导的B细胞死亡过程。在这建议，他将测试的假设，“异常调节LVA 钙通道通过细胞因子和其他因素改变B细胞钙稳态，使这些细胞倾向于进一步毒性，引起B细胞胰岛炎时的破坏。“拟议研究的目的包括：确定LVA钙通道介导钙内流的作用以及胰腺B细胞的凋亡。 LVA Ca 2+通道拮抗剂将是用于评价LVA Ca 2+通道在基础、葡萄糖和去极化刺激的Ca 2+内流。 LVA Ca ~（2+）通道在诱导的时间和剂量依赖性DNA断裂和细胞死亡还将研究细胞因子。 2)要从胰岛素分泌细胞系INS-1。通过RT-PCR方法，我们将推断， LVA Ca 2+的推定α 1亚基的核苷酸序列并在非洲爪蟾卵母细胞中表达。 3)为了研究 LVA钙离子通道调节。调查人员将研究如何细胞因子和性激素调节LVA Ca 2+通道的表达，糖尿病和非糖尿病动物模型。本研究将提供对选择性B细胞白血病发病机制的重要见解在人胰岛素依赖型糖尿病中的作用。