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

靶向雌激素受体以保护糖尿病患者的功能性 β 细胞群

基本信息

批准号：
8545806
负责人：
Franck Mauvais-Jarvis
金额：
$ 33.44万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8545806
关键词：
Acute Alleles Anabolism Apoptosis Apoptotic Beta Cell Cell Survival Cells Collaborations Coupled Data Development Diabetes Mellitus Diabetic mouse Dose Endothelial Cells Engraftment Enterochromaffin Cells Estradiol Estrogen Receptors Estrogens Exhibits Failure Female Funding GTP-Binding Proteins Glucose Goals Graft Survival Grant Hormones Human Hyperglycemia Hypoxia Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Knowledge Laboratories Mediating Membrane Mus Non-Insulin-Dependent Diabetes Mellitus Outcome Peptides Physiological Qualifying Reagent Receptor Activation Relative (related person)Reporting Research Rodent Model Role Therapeutic Therapeutic Index Tissues Translating Transplantation United States National Institutes of Health Xenograft procedure base cell type diabetic patient glucagon-like peptide hyperglucagonemia improved in vivo innovation insulin secretion islet mouse model novel prevent receptor reproductive sex single molecule success synergism type I diabetic

项目摘要

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.

描述（由适用提供）：这是R01DK074970的首次竞争续订“雌激素受体在β细胞生存和胰岛素分泌中的作用”。我们的实验室是一个先驱，证明了雌性马龙17？ - 雌二醇（E2）保护小鼠体内凋亡的胰岛效果不受凋亡。我们已经表明，E2抗凋亡保护是通过核外雌激素受体（ER）介导的。我们还报告说，这些ERS的激活增强了胰岛胰岛素的生物合成并阻止体内胰岛脂肪毒性，从而阻止了2型糖尿病啮齿动物模型中的细胞衰竭。这种竞争性更新的重点是ER在胰岛素缺乏糖尿病的移植过程中ERS在胰岛植入术中的作用。胰岛移植（PIT）是重要的治疗方法 1型糖尿病（T1D）。但是，胰岛血运重建和植入的失败限制了其宽度应用。暴露于多种侮辱的移植胰岛可能会在血运重建之前被破坏。我们的新初步数据表明，在T1D的小鼠模型中，ER激活永久改善了人类胰岛的植入，这些机制涉及急性抑制胰岛移植缺氧和凋亡以及对高葡萄糖血症的急性抑制。这与随后的胰岛血运重建和功能质量的增加有关。在此应用中，我们建议探索在移植物中，使用条件在这些细胞中的有条件的null等位基因的小鼠，探索了移植物，受体�-细胞和内皮细胞对胰岛血运重建的贡献。 We also propose to explore the synergy between estrogen and glutagon-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.