Beta Cell Regeneration by an Epigenetic Pathway

描述(申请人提供)：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，每年在相关医疗保健上花费超过1000亿美元。糖尿病最终是由于有功能的β细胞数量不足所致。人类β细胞的再生或增殖在糖尿病条件下是极其缓慢和低效的，这为再生β细胞以改善糖尿病提供了巨大的障碍。在这方面，编码核蛋白menin的多发性内分泌肿瘤1型基因(MEN1)的突变是唯一被证实的有效促进人类β细胞增殖的方法。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切除可以逆转喂食高脂饮食(HFD)小鼠先前存在的高血糖。然而，抑制薄荷素是如何导致β细胞再生增加的还不是很清楚。最近，我们帮助解决了Menin和Jund的共晶结构，发现Menin与Jund结合有一个很深的口袋，并抑制Jund的磷酸化。此外，Menin和Jund都与内源性细胞周期蛋白D1基因的启动子结合，该基因是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，以及促进增殖的途径。因此，我们有理由假设，在正常情况下，薄荷素通过抑制Jund来抑制细胞周期蛋白D1的表达，也可以通过抑制其他增殖基因和HH信号，与组蛋白精氨酸甲基转移酶共同抑制β细胞的再生。为了验证这些假说，我们提出了三个目标：目的1.研究menin如何通过调节Jund来调控细胞周期蛋白D1的表达。目的2.在小鼠模型中检测组蛋白精氨酸甲基转移酶在控制基因表达、β细胞再生和糖耐量中的作用。目的3.研究脑膜素介导的HH信号在控制β细胞再生中的作用。这些研究很可能会瓦解 β细胞再生的新机制，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。

DESCRIPTION (provided by applicant): 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, and 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.