Beta Cell Regeneration by an Epigenetic Pathway

通过表观遗传途径进行β细胞再生

• 批准号: 8631453
• 负责人: Xianxin Hua
• 金额: $ 34.8万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631453
• 关键词: Ablation; Acute; Adult; Affect; Beta Cell; Binding; CCND1 gene; Cell Line; Cell Proliferation; Cyclin D1; Development; Diabetes Mellitus; Diabetic mouse; Diet; Epigenetic Process; Erinaceidae; Excision; Fatty acid glycerol esters; Gene Expression; Genes; Gestational Diabetes; Health Care Costs; Healthcare; Human; Hyperglycemia; Insulin; Insulin-Dependent Diabetes Mellitus; Lead; Mediating; Menin; Multiple Endocrine Neoplasia Type 1; Mus; Mutation; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Protein; Pathway interactions; Phosphorylation; Production; Protein-Arginine N-Methyltransferase; Proteins; Public Health; Regulation; Repression; Role; Stress; Structure; Testing; Therapeutic; base; cell growth; cost; diabetic; feeding; glucose tolerance; innovation; insight; islet; mouse model; novel; prevent; promoter; public health relevance; smoothened signaling pathway

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.

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， 每年有1000亿美元用于相关的医疗保健。 糖尿病最终是由于缺乏足够的 功能性β细胞人β细胞的再生或增殖在体内是极其缓慢和低效的。 糖尿病病症，对再生β细胞以改善糖尿病提出了很大的障碍。 在这 关于这一点，多发性内分泌瘤1型基因（MEN1）突变，该基因编码核内分泌瘤。 menin蛋白是唯一经遗传学证实的有效增加β细胞增殖的方法， 人类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切除逆转了喂食高血糖症小鼠的预先存在的高血糖症。 高脂饮食（HFD）。然而，目前还不清楚抑制menin是如何导致β 细胞再生 最近，我们帮助解决了menin和JunD的共晶结构，发现 menin具有用于结合JunD的深口袋并抑制JunD磷酸化。此外，两名男子 JunD与内源性细胞周期蛋白D1基因的启动子结合，后者是β细胞中的一种关键增殖因子。 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）信号传导（一种促增殖途径）的表达。 因此，这是合理的假设，menin通常通过抑制细胞周期蛋白D1的表达， JunD，也抑制其他增殖基因和Hh信号，与组蛋白精氨酸一致 甲基转移酶，以抑制β细胞再生。为了检验这些假设，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。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。 目标3. 研究menin介导的Hh信号调节， 控制β细胞再生 这些研究可能会揭示β细胞的新机制， 再生，为开发一种新的基于menin途径的治疗糖尿病的疗法铺平了道路。