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疾病。胰岛β细胞功能亢进导致蛋白质错误折叠、内质网（EndRetic）应激并激活未折叠蛋白反应（UPR）。内质网相关蛋白降解（ERAD）途径被破坏，该途径通常去除错误折叠的蛋白。如果蛋白质错误折叠没有解决，β细胞就会死亡。因此，为了保护T2D中的功能性β细胞群，我们必须探索新的治疗方法来增强β细胞错误折叠蛋白的去除。我们的实验室率先表明，雌性雌激素通过直接激活雌激素受体（ER）α、ERβ和G蛋白偶联ER，保护两种性别小鼠的胰岛β细胞免受促凋亡损伤。我们发现这些影响存在于人类胰岛中。在该R01DK074970的上一个资助期内，我们进行了新的、意义深远的观察，即雌激素激活ERα可防止严重蛋白质错误折叠期间EndRetic应激对β细胞的破坏。本申请的具体目的是在小鼠模型和人胰岛中使用FDA批准的雌激素，以1）确定β细胞中ERα的活化通过增加ERAD途径减弱EndoRetic应激的机制，从而促进错误折叠的蛋白质降解，和2）剖析巴多昔芬作为ERα激动剂促进具体目的1中描述的效果的机制，选择性地在雌性而不是雄性的β细胞中。

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.