Beta Cell Regeneration by an Epigenetic Pathway

项目摘要 糖尿病，包括1型(T1D)和2型(T2D)糖尿病，是一个主要的公共卫生问题，造成超过 每年1000亿美元用于相关的医疗保健。糖尿病最终是由数量不足的 功能正常的β细胞。人类β细胞的再生或增殖极其缓慢和低效。 糖尿病的状况，给再生改善糖尿病的β细胞带来了很大的障碍。在这件事上 关于，编码核的多发性内分泌腺瘤病1型基因(MEN1)的突变 蛋白薄荷素，是唯一被基因证实的有效促进β细胞增殖的方法 人类。梅宁在生理上受到抑制，可以促进β细胞的增殖，从而预防妊娠期糖尿病。 我们最近的发现表明，急性MEN1切除可以逆转喂食小鼠先前存在的高血糖 高脂饮食(HFD)。然而，目前还不清楚抑制薄荷素是如何导致β增加的。 细胞再生。最近，我们帮助解决了薄荷和荣德的共晶结构，发现 Menin有一个很深的口袋与Jund结合，并抑制Jund的磷酸化。而且，这两个人 而Jund与内源性细胞周期蛋白D1基因的启动子结合，后者是β细胞中的关键增殖因子。 此外，还发现脑膜素与组蛋白精氨酸甲基转移酶相互作用，导致抑制。 其他促增殖基因的表达和Hedgehog(HH)信号，促增殖途径。 因此，假设薄荷素通常通过抑制Cyclin D1的表达来抑制细胞周期蛋白D1的表达是合理的 Jund，并与组蛋白精氨酸协同抑制其他增殖基因和HH信号 甲基转移酶，以抑制β细胞再生。为了验证这些假设，我们提出了三个目标： 目的1.研究Menin如何通过调节Jund调控细胞周期蛋白D1的表达。目标2.检查 组蛋白精氨酸甲基转移酶在控制基因表达、β细胞再生和 小鼠模型中的葡萄糖耐量。目的3.研究脑膜素对HH信号的调节作用 控制β细胞再生。这些研究可能会揭开β细胞的新机制。 再生，为开发基于薄荷素途径的治疗糖尿病的新疗法铺平了道路。

Project Summary Diabetes, including type 1 (T1D) and type 2 (T2D) diabetes, is a major public health problem, costing over $100 billion annually in related health care. Diabetes eventually results from an inadequate number of functional beta cells. Regeneration or proliferation of human beta cells is extremely slow and inefficient in diabetic conditions, presenting a great hurdle to regenerate beta cells for ameliorating diabetes. In this regard, mutations in the multiple endocrine neoplasia type 1 gene (MEN1), which encodes the nuclear protein menin, is the only genetically proven means to effectively increase proliferation of beta cells in humans. Menin is physiologically inhibited to increase beta cell proliferation to prevent gestational diabetes. Our recent findings demonstrate that acute Men1 excision reverses pre-existing hyperglycemia in mice fed with high-fat diet (HFD). However, it is not well understood how inhibition of menin leads to increased beta cell regeneration. Recently, we helped solve the co-crystal structure of menin and JunD, and found that menin harbors a deep pocket for binding to JunD and inhibits JunD phosphorylation. Moreover, both menin and JunD bind to the promoter of the endogenous cyclin D1 gene, a crucial proliferation factor in beta cells. Furthermore, menin was found to interact with a histone arginine methyltransferase, leading to suppression of expression of other pro-proliferative genes and Hedgehog (Hh) signaling, a pro-proliferative pathway. Thus, it is plausible to hypothesize that menin normally suppresses expression of cyclin D1 via repressing JunD, and also represses other proliferative genes and Hh signaling, in concert with histone arginine methyltransferase, to suppress beta cell regeneration. To test these hypotheses, three aims are proposed: Aim 1. Investigate how menin controls expression of cyclin D1 via regulating JunD. Aim 2. Examine the role of the histone arginine methyltransferase in controlling gene expression, beta cell regeneration, and glucose tolerance in mouse models. Aim 3. Investigate menin-mediated regulation of Hh signaling in controlling beta cell regeneration. These studies will likely unravel novel mechanisms of beta cell regeneration, paving the way to develop a novel menin pathway-based therapy to treat diabetes.