Repurposing estrogens to improve pancreatic islet transplantation

抽象的。 这项应用的目标是使用小鼠模型来阐明雌激素通过以下方式发挥作用的机制 雌激素受体(ER)S途径改善胰岛氧合、血运重建和功能质量 胰岛移植(PIT)。改善1型糖尿病(T1D)的PIT结局是 国家卫生研究院。我们必须探索新的、简单和安全的治疗方法来抑制胰岛细胞凋亡，同时 在移植后即刻促进胰岛氧合和血运重建。我们的实验室是 第一个表明女性激素17β-雌二醇(E_2)通过雌激素保护胰岛β-细胞免于凋亡 受体和人类胰岛中。我们的新的初步数据表明，E2增强了胰岛的氧合作用， PIT期间的血运重建和功能块。我们需要确定实际的细胞靶标和分子 急诊室用来促进这些行动的途径。本申请的具体目的是：1)阐明 ERs条件零等位基因在β细胞移植胰岛中的作用 细胞(βerko)。我们将探索一种新的范式，在这种范式中，ERα在移植的β细胞中被激活 通过AMP激活的蛋白激酶(AMPK)和远离低氧诱导的胰岛代谢 因子-1(HIF1)改善胰岛在低氧状态下的性能。2)定义ER激活在 受体内皮细胞利用这些细胞中ER条件零等位基因的小鼠移植胰岛 (VENERKO)。我们将探索一种新的概念，即受体小鼠内皮细胞中ERα的激活 通过内皮型一氧化氮合酶(ENOS)促进急性血管扩张和氧合 血管内皮细胞生长因子-A(VEGF-A)的血管重建。

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).