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，每年在相关卫生保健方面花费超过1000亿美元。糖尿病的最终结果是功能性β细胞数量不足。在糖尿病患者中，人类β细胞的再生或增殖极其缓慢和低效，这给改善糖尿病的β细胞再生带来了很大的障碍。在这方面，编码核蛋白menin的多发性内分泌瘤1型基因（MEN1）的突变是唯一经过遗传学证明的有效增加人类β细胞增殖的手段。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切除可逆转高脂肪饮食（HFD）小鼠先前存在的高血糖。然而，目前尚不清楚抑制menin如何导致β细胞再生增加。最近，我们帮助解决了menin和JunD的共晶结构，发现menin有一个深口袋，可以结合JunD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，而细胞周期蛋白D1基因是β细胞中至关重要的增殖因子。此外，menin被发现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）信号的表达，以及促增殖途径。因此，我们有可能假设menin通常通过抑制JunD来抑制cyclin D1的表达，并抑制其他增殖基因和Hh信号，与组蛋白精氨酸甲基转移酶一起抑制β细胞再生。为了验证这些假设，提出了三个目标：目标1。探讨menin如何通过调节JunD调控cyclin D1的表达。目标2。在小鼠模型中研究组蛋白精氨酸甲基转移酶在控制基因表达、β细胞再生和葡萄糖耐量中的作用。目标3。研究Hh信号在控制β细胞再生中的menin介导调节。这些研究很可能会被解开

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.