Repurposing estrogens to improve pancreatic islet transplantation

摘要。 本申请的目的是使用小鼠模型来阐明雌激素作用的机制， 雌激素受体（ER）的方式，改善胰岛氧合，血管重建和功能质量， 胰岛移植（PIT）。改善1型糖尿病（T1 D）的PIT结果是本研究的主要目标。 国家卫生研究院我们必须探索新的、简单的、安全的治疗方法来抑制胰岛细胞凋亡， 促进移植后即刻胰岛氧合和血管再生。本实验室 第一个表明雌性激素17β-雌二醇（E2）通过雌激素保护胰岛β细胞免于凋亡 受体和人类胰岛中。我们新的初步数据表明，E2增强胰岛氧合， 血运重建和功能性肿块。我们需要确定真正的细胞目标和分子 环境要求使用的途径来促进这些行动。本申请的具体目的是1）阐明 ER激活在移植β细胞胰岛植入中的作用，使用ER条件无效等位基因的小鼠， 细胞（βERKO）。我们将探索一种新的范式，在这种范式中，移植β细胞中的ERα激活 通过AMP激活的蛋白激酶（AMPK）的方式编程胰岛代谢， 因子-1（HIF 1），以改善缺氧期间的胰岛性能。2)定义ER激活在以下方面的贡献： 受体内皮细胞向胰岛移植，使用这些细胞中ER的条件无效等位基因的小鼠 （VENERKO）。我们将探索一个新的概念，其中受体小鼠内皮细胞中的ERα激活 通过内皮型一氧化氮合酶（eNOS）促进急性血管舒张和氧合， 通过血管内皮生长因子-A（VEGF-A）的方式进行血运重建。

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).