Targeting Estrogen Receptors to Protect Functional Beta-cell Mass in Diabetes

描述(申请人提供)：这是R01DK074970《雌激素受体在β细胞存活和胰岛素分泌中的作用》第一次竞争性更新的重新提交。我们实验室率先在体内证明了雌性激素17？-雌二醇(E_2)对小鼠胰岛细胞的凋亡有保护作用。我们已经证明，E2的抗凋亡保护作用是通过核外雌激素受体(ER)S介导的。我们还报道了在2型糖尿病啮齿动物模型中，这些ER的激活促进了胰岛胰岛素的生物合成，并在体内阻止了胰岛脂肪毒性，从而防止了细胞衰竭。这一竞争性的更新集中在胰岛素缺乏性糖尿病患者移植期间内质网在胰岛移植中的作用。胰岛移植(PIT)是一种重要的治疗手段 1型糖尿病(T1D)。然而，胰岛血运重建和移植的失败限制了其广泛应用。移植的胰岛暴露在多次侮辱下，可能在血运重建发生之前被破坏。我们新的初步数据表明，在T1D小鼠模型中，ER的激活通过多种机制永久性地改善了人胰岛在PIT期间的植入，包括急性抑制胰岛移植物的缺氧和凋亡，以及急性抑制高血糖素血症。这与胰岛血运重建和功能质量的增加有关。在这项应用中，我们建议利用移植物细胞、受体细胞和内皮细胞中的ER？在这些细胞中的条件零等位基因的小鼠来探讨这些细胞中的ER？在PIT期间对胰岛血管重建的贡献。我们还建议使用一种将E2和GLP-1结合在一个单分子中的新化合物来探索雌激素和胰高血糖素样肽-1(GLP-1)在糖尿病小鼠PIT模型中在人类胰岛存活和血管重建中的协同作用，该化合物允许靶向E2，在膜GLP-1受体存在的地方，细胞和内皮细胞，并远离妇科组织。 公共卫生相关性：这项拨款中提议的研究将产生重大影响，因为当成功完成后，它将为改善1型糖尿病患者的胰岛植入提供一种快速可用的治疗替代方案。

DESCRIPTION (provided by applicant): This is the resubmission of the first competitive renewal of R01DK074970 "Role of estrogen receptors in beta- cell survival and insulin secretion". Our laboratory was a pioneer in demonstrating that the female hormone 17¿-estradiol (E2) protects islet ¿-cells from apoptosis in vivo in mice. We have shown that E2 anti-apoptotic protection is mediated via extranuclear estrogen receptor (ER)s. We also reported that activation of these ERs enhances islet insulin biosynthesis and prevents islet lipotoxicity in vivo thus preventing ¿-cell failure in rodent models of type 2 diabetes. This competitive renewal focuses on the role of ERs in pancreatic islet engraftment during transplantation in insulin deficient diabetes. Pancreatic islet transplantation (PIT) is an important therapeutic approach in type 1 diabetes (T1D). However, the failure of islet revascularization and engraftment limits its widespread application. The transplanted islets exposed to multiple insults may be destroyed before revascularization occurs. Our new preliminary data suggest that ER activation permanently improves human islet engraftment during PIT in a mouse model of T1D via multiple mechanisms involving an acute suppression of islet graft hypoxia and apoptosis and an acute suppression of hyperglucagonemia. This is associated to a latter increase in islet revascularization and functional mass. In this application we propose to explore the contributions of the ER¿ in graft ¿-cells, recipient ¿-cells and endothelial cells to islet revascularization during PIT, using mice with conditional null alleles of ER¿ in these cells. We also propose to explore the synergy between estrogen and glucagon-like peptide-1 (GLP-1) in human islet survival and revascularization in a diabetic mouse model of PIT using a novel compound combining E2 and GLP-1 in a single molecule which allows the targeting of E2 where membrane GLP-1 receptors are present, the ¿-cells and the endothelial cells, and away from gynecological tissues. PUBLIC HEALTH RELEVANCE: The research proposed in this grant will have a significant impact because when successfully completed it will provide a rapidly available therapeutic alternative to improve pancreatic islet engraftment in type 1 diabetic patients.