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

描述（由申请人提供）：这是R 01 DK 074970“雌激素受体在β细胞存活和胰岛素分泌中的作用”首次竞争性更新的重新提交。我们的实验室是证明雌性激素17 <$-雌二醇（E2）在小鼠体内保护胰岛<$-细胞免于凋亡的先驱。我们已经证明E2的抗凋亡保护作用是通过雌激素受体介导的。我们还报道了在2型糖尿病的啮齿动物模型中，这些ER的激活增强了胰岛胰岛素的生物合成，并防止了体内胰岛脂毒性，从而防止了胰岛细胞衰竭。这项竞争性更新的重点是ER在胰岛素缺乏型糖尿病移植过程中胰岛植入中的作用。 胰岛移植（PIT）是治疗胰腺炎的重要方法。 1型糖尿病（T1 D）。然而，胰岛血管重建和植入的失败限制了其广泛应用。暴露于多次损伤的移植胰岛可能在血管重建发生之前被破坏。 我们的新的初步数据表明，ER激活永久改善人类胰岛移植期间在T1 D小鼠模型PIT通过多种机制，包括急性抑制胰岛移植缺氧和细胞凋亡和急性抑制高胰高血糖素血症。这与胰岛血运重建和功能质量的增加有关。在本申请中，我们建议使用在这些细胞中具有ER <$的条件无效等位基因的小鼠，探索在PIT期间移植物<$-细胞、受体<$-细胞和内皮细胞中ER <$对胰岛血管重建的贡献。我们还建议在PIT的糖尿病小鼠模型中，使用一种将E2和GLP-1结合在单个分子中的新型化合物来探索雌激素和胰高血糖素样肽-1（GLP-1）在人胰岛存活和血管重建中的协同作用，该化合物允许靶向膜GLP-1受体存在的E2，- 细胞和内皮细胞，并远离妇科组织。

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.