PRESERVATION OF BETA CELL FUNCTION BY CALBINDIN D28K

CALBINDIN D28K 保护 β 细胞功能

• 批准号: 2906347
• 负责人: SYLVIA S CHRISTAKOS
• 金额: $ 14.75万
• 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 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2906347
• 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.

有人建议可以利用最近的 已开发且更容易获得的 β 细胞系作为替代方案 胰岛或整个胰腺移植治疗糖尿病。 我们最近报道了稳定转染和过度表达 大鼠 β 细胞系 RIN 1046-38 中的钙结合蛋白钙结合蛋白 导致胰岛素 mRNA 显着增加（超过 20 倍） 大多数克隆）以及胰岛素含量、释放和转录。 这些研究为钙结合蛋白在β中的作用提供了直接证据 可能具有治疗相关性的细胞功能。然而，RIN 细胞 对葡萄糖的反应很少或没有。用于移植 治疗时，利用具有功能的 β 细胞非常重要 接近正常的β细胞。 因此，我们在此探索性建议 拨款进一步研究钙结合蛋白在β细胞中的作用 beta-HC 细胞对葡萄糖和其他促分泌剂有反应。 具体来说，将检查 β-HC 细胞中钙结合蛋白的作用 基础胰岛素 mRNA、基础胰岛素含量、释放和 转录以及对促分泌素的反应。 此外，我们还将确定钙结合蛋白是否已被 据报道可以防止许多不同的细胞凋亡 细胞，可以防止细胞因子和链脲佐菌素 (STZ) 诱导的 破坏大鼠β细胞。 可能涉及的机制 将检查钙结合蛋白的保护作用，包括抑制作用 刺激一氧化氮产生并抑制钙蛋白酶或 白细胞介素 1-β 转换酶蛋白酶活性。 这些发现 对预防 β 细胞具有治疗意义 破坏可能对β细胞有重要的应用 移植。