Targeting the estrogen receptor-α to protect functional β-cell mass in women

2型糖尿病(T2D)被认为是一种蛋白质错误折叠障碍。胰岛β细胞功能亢进导致蛋白质错误折叠、内质网应激并激活未折叠蛋白反应。内质网相关蛋白降解(ERAD)途径被破坏，该途径通常会去除错误折叠的蛋白质。如果蛋白质错误折叠得不到解决，β-细胞就会死亡。因此，为了保护T2D中的功能性β细胞团，我们必须探索新的治疗方法来加强错误折叠蛋白β细胞的清除。本实验室率先证明雌性雌激素通过直接激活雌激素受体(ER)βα、ERβ和G蛋白偶联ER来保护胰岛细胞免受促凋亡损伤。我们证明了这些效应存在于人类的胰岛中。在R01DK074970的上一次资助期间，我们进行了新的和深远的观察，即雌激素激活ERα可以防止蛋白质在严重错误折叠过程中受到EndRetic应激的β细胞的破坏。这项应用的具体目的将在小鼠模型和人类胰岛中使用美国食品和药物管理局批准的雌激素，以1)确定ERα在β细胞中的激活通过增加ERAD途径从而促进错误折叠的蛋白质降解来减轻内质网应激的机制，以及2)剖析巴多昔芬作为ERα激动剂以促进特定目标1中所述的作用的机制，该机制选择性地在雌性而不是男性的β细胞中发挥作用。

Type 2 diabetes (T2D) is considered a protein misfolding disorder. Hyperfunction of the islet β-cells leads to protein misfolding, endoplasmic reticulum (EndRetic) stress and activates the unfolded protein response (UPR). There is disruption of the endoplasmic reticulum-associated protein degradation (ERAD) pathway which normally removes misfolded proteins. If protein misfolding is not resolved, β-cells die. Thus, to protect functional β-cell mass in T2D, we must explore new therapeutic approaches to enhance the removal of misfolded proteins β-cells. Our laboratory was a pioneer in showing that the female estrogens protect islet β-cells from pro-apoptotic injuries in mice of both sexes via direct activation of estrogen receptor(ER)α, ERβ and the G-protein coupled ER. We showed that these effects are present in human islets. During the previous funding period of this R01DK074970, we made the new and far-reaching observation that estrogens activation of ERα prevents β-cell destruction from EndRetic stress during severe protein misfolding. The specific aims of this application will use FDA-approved estrogens in mouse models and human islets to 1) determine the mechanism by which activation of ERα in β-cells attenuates EndoRetic stress by increasing the ERAD pathway, thus promoting misfolded protein degradation, and 2) dissect the mechanism by which bazedoxifene acts as ERα agonist to promote the effect described in specific aim 1, selectively in β-cells of females but not males.