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: 9085290
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9085290
• 关键词: Ablation; Acute; Adult; Affect; Beta Cell; Binding; CCND1 gene; Cell Line; Cell Proliferation; Cyclin D1; Development; Diabetes Mellitus; Diabetic mouse; Epigenetic Process; Erinaceidae; Excision; Gene Expression; Genes; Gestational Diabetes; Health; Health Care Costs; Healthcare; High Fat Diet; Human; Hyperglycemia; Insulin; Insulin-Dependent Diabetes Mellitus; Lead; LoxP-flanked allele; 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; smoothened signaling pathway

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.

描述（由申请人提供）：包括1型（T1D）和2型（T2D）糖尿病的糖尿病是一个主要的公共卫生问题，每年在相关的医疗保健中耗资超过1000亿美元。糖尿病最终是由于功能β细胞数量不足而导致的。人β细胞的再生或增殖在糖尿病状况下极低且效率低下，为改善糖尿病的β细胞带来了一个巨大的障碍。在这方面，编码编码核蛋白梅宁的多种内分泌肿瘤1型基因（MEN1）中的突变是唯一有效地增加人类β细胞增殖的遗传证明的手段。梅宁在生理上被抑制以增加β细胞增殖以防止妊娠糖尿病。我们最近的发现表明，急性MEN1切除会逆转以高脂饮食（HFD）喂养的小鼠中预先存在的高血糖症。但是，尚不清楚抑制Menin是如何导致β细胞再生增加的。最近，我们帮助解决了Menin和Jund的共晶结构，发现Menin携带着一个深层口袋，可与Jund结合并抑制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，这是β细胞中关键的增殖因子。此外，发现Menin与组蛋白精氨酸甲基转移酶相互作用，从而抑制其他促增殖基因和刺猬（HH）信号传导的表达，以及促增强的途径。因此，假设Menin通常通过抑制Jund抑制Cyclin D1的表达是合理的，并且还抑制其他增殖基因和HH信号传导，与组蛋白精氨酸甲基转移酶一起抑制β细胞再生。为了检验这些假设，提出了三个目标：目标1。研究梅宁如何通过调节Jund来控制细胞周期蛋白D1的表达。 AIM 2。检查组蛋白精氨酸甲基转移酶在控制基因表达，β细胞再生和葡萄糖耐受性中的作用。 AIM 3。研究MENIN介导的HH信号调节在控制β细胞再生中。这些研究可能会解散 β细胞再生的新型机制，为开发一种新型Menin途径治疗糖尿病的疗法铺平了道路。