Repurposing estrogens to improve pancreatic islet transplantation

重新利用雌激素来改善胰岛移植

基本信息

批准号：
9185114
负责人：
Franck Mauvais-Jarvis
金额：
$ 36.73万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9185114
关键词：
5&apos -AMP-activated protein kinase Acute Agonist Alleles Anabolism Apoptosis Beta Cell Blood flow Cells Chronic Collaborations Data Development Diabetic mouse Endothelial Cells Engraftment Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Failure Female Fostering Foundations GPER gene Glucose Goals Grant Hormones Human Hypoxia Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Knowledge Laboratories Mediating Membrane Metabolism Molecular Mus NOS3 gene Non-Insulin-Dependent Diabetes Mellitus Nuclear Outcome Pathway interactions Performance Pregnancy Property Qualifying Reagent Research Rodent Model Role Therapeutic Tissues Transplantation United States National Institutes of Health VEGFA gene Vascular Endothelial Growth Factors Vascularization Vasodilation Xenograft procedure base cellular targeting defined contribution hypoxia inducible factor 1 improved improved outcome in vivo islet mouse model novel novel strategies prevent programs

项目摘要

ABSTRACT. The goal of this application is to use a mouse model to elucidate the mechanisms by which estrogen action, by way of the estrogen receptor(ER)s, improves islet oxygenation, revascularization and functional mass during pancreatic islet transplantation (PIT). Improving PIT outcome in type 1 diabetes (T1D) is a major goal of the NIH. We must explore new, simple and safe therapeutic approaches to suppress islet apoptosis while promoting islet oxygenation and revascularization in the immediate post-transplant period. Our laboratory was the first to show that the female hormone 17β-estradiol (E2) protects islet β-cells from apoptosis via estrogen receptors and in human islets. Our new preliminary data demonstrates that E2 enhances islet oxygenation, revascularization and functional mass during PIT. We need to identify the actual cellular targets and molecular pathways used by ERs to promote these actions. The specific aims of this application are to 1) Elucidate the role ERs activation in graft β-cells to islet engraftment using mice with conditional null allele of ERs in these cells (βERKO). We will explore a novel paradigm in which paradigm that ERα activation in graft β-cells programs islet metabolism by way of AMP-activated protein kinase (AMPK) and away from hypoxia-inducible factor-1 (HIF1) to improve islet performance during hypoxia. 2) Define the contribution of ERs activation in recipient endothelial cells to islet engraftment using mice with conditional null allele of ERs in these cells (VENERKO). We will explore a novel concept in which ERα activation in recipient mouse endothelial cells promotes acute vasodilation and oxygenation via endothelial nitric oxide synthase (eNOS) and delayed revascularization by way of vascular endothelial growth factor-A (VEGF-A).

抽象的。该应用的目标是使用小鼠模型来阐明雌激素作用的机制，通过雌激素受体 (ER) 的方式，改善胰岛氧合、血运重建和功能质量改善 1 型糖尿病 (T1D) 的胰岛移植 (PIT) 结局是该项目的主要目标。 NIH。我们必须探索新的、简单且安全的治疗方法来抑制胰岛细胞凋亡，同时在移植后立即促进胰岛氧合和血运重建。第一个证明女性激素 17β-雌二醇 (E2) 通过雌激素保护胰岛 β 细胞免于凋亡我们新的初步数据表明 E2 可以增强胰岛的氧合作用， PIT 期间的血运重建和功能质量我们需要确定实际的细胞靶标和分子。 ER 用于促进这些行动的途径本申请的具体目标是 1) 阐明使用具有 ER 条件无效等位基因的小鼠，ER 激活在移植 β 细胞到胰岛移植中的作用我们将探索一种新的范例，其中 ERα 在移植物 β 细胞中激活。通过 AMP 激活蛋白激酶 (AMPK) 编程胰岛代谢，避免缺氧诱导因子 1 (HIF1) 可改善缺氧期间的胰岛性能 2) 定义 ER 激活的贡献。使用这些细胞中 ER 条件无效等位基因的小鼠将受体内皮细胞移植到胰岛（VENERKO）我们将探索受体小鼠内皮细胞中 ERα 激活的新概念。通过内皮一氧化氮合酶 (eNOS) 促进急性血管舒张和氧合，并延迟通过血管内皮生长因子-A (VEGF-A) 进行血运重建。