PRESERVATION OF BETA CELL FUNCTION BY CALBINDIN D28K

CALBINDIN D28K 保护 β 细胞功能

• 批准号: 2794813
• 负责人: SYLVIA S CHRISTAKOS
• 金额: $ 14.32万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2794813
• 关键词: apoptosis; calbindin; calpain; cell growth regulation; hormone biosynthesis; insulin; nitric oxide; pancreatic islet function; pancreatic islets; tissue /cell culture; transfection

It has been suggested that it may be possible to utilize the recently developed and more readily available beta cell lines as an alternative to islets or whole pancreas for transplantation therapy of diabetes. We recently reported that stable transfection and overexpression of the calcium binding protein calbindin in the rat beta cell line RIN 1046-38 results in a marked increase in insulin mRNA (greater than 20 fold for most clones) as well as insulin content, release and transcription. These studies provided direct evidence for a role for calbindin in beta cell function which may have therapeutic relevance. However, RIN cells have little or no responsiveness to glucose. For transplantation therapy, it will be important to utilize beta cells with functions approximating normal beta cells. Thus we propose in this exploratory grant to further examine the role of calbindin in the beta cell using beta-HC cells which respond to glucose and other secretagogues. Specifically, beta-HC cells will be examined for the effect of calbindin on basal insulin mRNA, on basal insulin content, release and transcription, and on the response to secretagogues. In addition we will also determine whether calbindin, which has been reported to protect against apoptotic death of a number of different cells, can protect against cytokine and streptozotocin (STZ) induced destruction of rat beta cells. Possible mechanisms involved in a protective effect of calbindin will be examined, including inhibition of stimulation of nitric oxide production and inhibition of calpain or interleukin 1-beta-converting enzyme protease activity. These findings would have therapeutic implications for the prevention of beta cell destruction which could have important application to beta cell transplantation.

有人建议可以使用最近 开发，更容易获得的β细胞系作为替代方案 到糖尿病移植治疗的胰岛或整个胰腺。 我们最近报道了稳定的转染和过表达 大鼠β细胞系RIN中的钙结合蛋白钙蛋白RIN 1046-38 导致胰岛素mRNA明显增加（大于20倍 大多数克隆）以及胰岛素含量，释放和转录。 这些研究提供了Calbindin在beta中的作用的直接证据 细胞功能可能具有治疗性相关性。但是，RIN细胞 对葡萄糖的反应几乎没有反应。用于移植 治疗，使用功能的β细胞很重要 近似正常β细胞。 因此，我们在此探索性中提出了建议 授予使用 对葡萄糖和其他促分子作出反应的β-HC细胞。 具体而言，将检查β-HC细胞的Calbindin的作用 在基底胰岛素mRNA上，基础胰岛素含量，释放和 转录，以及对秘密的反应。 此外，我们还将确定Calbindin是否已经 报告预防许多不同的凋亡死亡 细胞，可以预防细胞因子和链蛋白酶（STZ）诱导的细胞 大鼠β细胞的破坏。 涉及的可能机制 Calbindin的保护作用将检查，包括抑制作用 刺激一氧化氮产生和抑制钙蛋白酶或 白介素1-β转化酶蛋白酶活性。 这些发现 对预防β细胞具有治疗意义 破坏可能对Beta细胞有重要应用的破坏 移植。