Small molecules for expansion of islet beta-cell mass in diabetes

项目摘要/摘要 糖尿病目前影响着9.3%的美国人口，每年在美国的医疗保健费用总计2450亿美元。 目前的糖尿病治疗方法在控制血糖和/或增强胰岛素的能力方面受到限制 灵敏度考虑到糖尿病成本和并发症的严重性， 是迫切需要的。1型糖尿病和2型糖尿病的共同缺陷是功能性胰腺炎。 胰岛β细胞团。一种治疗性干预措施，可抑制产生胰岛素的胰腺β细胞 代表着糖尿病的治愈方法 我们建议开发两种不同的分子支架，并在体内证明了刺激细胞增殖的概念。 胰腺β细胞增殖。一系列苯基苯甲酰胺，在一个无关的肝脂肪变性中发现 筛选，发现刺激啮齿动物，分离的大鼠和人类胰岛中的选择性β细胞增殖， 评估和优化功效和转化潜力。第二个系列-色烯酮， 在Nkx6.1启动子筛选中发现，已显示出在啮齿动物中强烈刺激β细胞增殖 和人类的小岛我们将对两种支架进行药物化学优化，以产生体内化学物质， 用于人类治疗用途的具有翻译潜力的探针。

Project Abstract/Summary Diabetes currently affects 9.3% of the U.S. population totaling $245 billion annually in U.S. healthcare costs. Current therapies for diabetes are limited in their ability to control blood glucose and/or enhance insulin sensitivity. Given the magnitude of diabetes costs and complications, new therapies with reduced side effects are urgently needed. The common defect in both type 1 and type 2 diabetes is the loss of functional pancreatic islet -cell mass. A therapeutic intervention that replenishes the insulin-producing pancreatic beta cells represents a cure for diabetes We propose to develop two distinct molecular scaffolds with demonstrated in vivo proof of concept for stimulating pancreatic beta-cell proliferation. A series of phenylbenzamides, discovered in an unrelated hepatic steatosis screen, were found to stimulate selective beta cell proliferation in rodents, isolated rat and human islets, and will be evaluated and optimized for efficacy and translational potential. The second series - chromenones, discovered in a Nkx6.1 promoter screen, have been shown to robustly stimulate beta-cell proliferation in rodent and human islets. We will perform medicinal chemistry optimization on both scaffolds to produce in vivo chemical probes with translational potential for human therapeutic use.