PRESERVATION OF BETA CELL FUNCTION BY CALBINDIN D28K

有人建议，也许可以利用最近的 开发和更容易获得的β细胞系作为替代 移植到胰岛或整个胰腺用于糖尿病的移植治疗。 我们最近报道了稳定转染和过表达的 大鼠β细胞系RIN 1046-38中的钙结合蛋白 导致胰岛素mRNA的显著增加（大于20倍， 大多数克隆）以及胰岛素含量、释放和转录。 这些研究为钙结合蛋白在β-半乳糖苷酶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 对葡萄糖几乎没有反应。用于移植 治疗，重要的是利用具有功能的β细胞， 接近正常的β细胞 因此，我们建议在这个探索性的 格兰特进一步研究钙结合蛋白在β细胞中的作用， 对葡萄糖和其他促分泌素有反应的β-HC细胞。 具体而言，将检查β-HC细胞的钙结合蛋白作用 对基础胰岛素mRNA、基础胰岛素含量、释放和 转录和对促分泌素的反应。 此外，我们还将确定是否钙结合蛋白，这已经被 据报道，它可以防止许多不同的细胞凋亡。 细胞，可以保护细胞因子和链脲佐菌素（STZ）诱导的 破坏大鼠的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 刺激一氧化氮产生和抑制钙蛋白酶，或 白细胞介素1-β-转化酶蛋白酶活性。 这些发现 对预防β细胞 对β细胞有重要应用的破坏 移植

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.