Beta Cell Regeneration by an Epigenetic Pathway

描述（由申请人提供）：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方面花费超过1000亿美元。糖尿病最终是由功能性β细胞数量不足引起的。人β细胞的再生或增殖在糖尿病病症中是极其缓慢和低效的，这对再生β细胞以改善糖尿病提出了很大的障碍。在这方面，编码核蛋白menin的多发性内分泌瘤1型基因（MEN1）的突变是唯一经遗传学证实的有效增加人类β细胞增殖的方法。Menin在生理上被抑制以增加β细胞增殖以预防妊娠糖尿病。我们最近的研究结果表明，急性Men1切除逆转了高脂饮食（HFD）喂养的小鼠中预先存在的高血糖症。然而，还不清楚menin的抑制如何导致β细胞再生增加。最近，我们帮助解决了menin和JunD的共晶体结构，并发现menin具有与JunD结合的深口袋并抑制JunD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，后者是β细胞中的一种关键增殖因子。此外，发现menin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和Hedgehog（Hh）信号传导的表达，以及促增殖途径。因此，这是合理的假设，menin通常通过抑制JunD抑制细胞周期蛋白D1的表达，也抑制其他增殖基因和Hh信号，与组蛋白精氨酸甲基转移酶，抑制β细胞再生。为了验证这些假设，提出了三个目标：目标1。研究menin如何通过调节JunD来调控cyclin D1的表达。目标二。研究组蛋白精氨酸甲基转移酶在小鼠模型中控制基因表达、β细胞再生和葡萄糖耐量的作用。目标3：研究menin介导的Hh信号调节在控制β细胞再生。这些研究很可能会解开 β细胞再生的新机制，为开发一种新的基于menin通路的治疗糖尿病的疗法铺平了道路。

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.