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）：糖尿病，包括 1 型 (T1D) 和 2 型 (T2D) 糖尿病，是一个重大的公共卫生问题，每年相关医疗保健费用超过 1000 亿美元。糖尿病最终是由功能性β细胞数量不足引起的。在糖尿病状况下，人类β细胞的再生或增殖极其缓慢且效率低下，这给再生β细胞以改善糖尿病带来了巨大障碍。在这方面，编码核蛋白menin的多发性内分泌肿瘤1型基因（MEN1）的突变是唯一经过基因验证的有效增加人类β细胞增殖的方法。 Menin 在生理上受到抑制，可增加 β 细胞增殖，从而预防妊娠糖尿病。我们最近的研究结果表明，急性 Men1 切除可逆转高脂饮食 (HFD) 喂养的小鼠先前存在的高血糖。然而，尚不清楚 menin 的抑制如何导致 β 细胞再生增加。最近，我们帮助解析了menin和JunD的共晶结构，发现menin具有一个深袋，可以与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，细胞周期蛋白 D1 基因是 β 细胞中的关键增殖因子。此外，menin 被发现与组蛋白精氨酸甲基转移酶相互作用，导致其他促增殖基因和 Hedgehog (Hh) 信号传导以及促增殖途径的表达受到抑制。因此，可以推测，menin 通常通过抑制 JunD 来抑制细胞周期蛋白 D1 的表达，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协同作用，从而抑制 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 来控制 cyclin D1 的表达。目标 2. 在小鼠模型中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量中的作用。目标 3. 研究 menin 介导的 Hh 信号传导调节控制 β 细胞再生。这些研究可能会揭开谜底 β细胞再生的新机制，为开发一种新的基于menin途径的糖尿病治疗方法铺平了道路。