Link of beta cell proliferation and type 2 diabetes to epigenetic regulation

β细胞增殖和2型糖尿病与表观遗传调控的联系

• 批准号: 7985014
• 负责人: Xianxin Hua
• 金额: $ 39.22万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7985014
• 关键词: Acute; Affect; Americas; Arginine; Benign; Beta Cell; Binding Proteins; Blood Glucose; Cell Cycle; Cell Proliferation; Cyclic AMP-Dependent Protein Kinases; Cyclin A; Diabetes Mellitus; Diabetic mouse; Diagnosis; Diet; Doctor of Medicine; Doctor of Philosophy; Endocrine Glands; Epigenetic Process; Excision; Fatty acid glycerol esters; Fright; Genes; Genetic Transcription; Gestational Diabetes; Glucose Intolerance; Goals; Histone H4; Histones; Hyperglycemia; Hyperplasia; Insulin; Islet Cell; Islets of Langerhans; Link; Liver; Mediating; Menin; Methylation; Methyltransferase; Multiple Endocrine Neoplasia Type 1; Mus; Mutation; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Protein; Nuclear Proteins; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Production; Protein-Arginine N-Methyltransferase; Regulation; Repression; Research; Resistance; Role; Signal Pathway; Signal Transduction; Streptozocin; United States; Widespread Disease; analog; base; cdc Genes; exenatide; feeding; glucagon-like peptide 1; improved; insight; mouse model; next generation; novel; peptide analog; prevent; public health relevance; tumorigenic

DESCRIPTION (provided by applicant): An adequate number of beta cells are required for production of a sufficient amount of insulin to maintain normoglycemia. Enhancing beta cell proliferation or regeneration can be an effective means to treat type 2 diabetes (T2D). Mutations in the multiple endocrine neoplasia type 1 gene (Men1), which encodes the nuclear protein menin, usually result in benign hyperplasia in several endocrine organs, such as pancreatic islets, but do not affect other organs, such as the liver. One of our long-term goals is to understand how menin regulates beta cell proliferation. Though it is attractive to tap into repressing menin to enhance beta cell regeneration and ameliorate diabetes, this was once thought problematic or unfeasible for fear of the potential tumorigenic effect from menin inhibition. However, recent and rapid research progress has altered this view. Menin is physiologically repressed to increase beta cell proliferation and prevent gestational diabetes. Our recent findings suggest that menin interplays with glucagon-like peptide 1 (GLP-1) signaling pathway, which promotes beta cell regeneration, to regulate gene transcription. For instance, menin suppresses, but GLP-1 increases cyclin A expression, linking menin to GLP-1 signaling. Menin interacts with PRMT5, a histone arginine methytransferase that represses gene transcription. Notably, Men1 excision not only renders mice resistant to streptozotocin (STZ)-induced hyperglycemia, but also ameliorates pre-existing hyperglycemia in STZ-induced diabetic mice. Our new results since the last submission also demonstrate that acute Men1 excision normalized pre-existing glucose intolerance in high-fat diet-fed mice. These findings strongly suggest that repressing menin can be a novel means to enhance beta cell regeneration and ameliorate diabetes. It is hypothesized that menin normally suppresses beta cell proliferation through repressing transcription of cell cycle regulators, such as GLP-1-induced cyclin A, in concert with epigenetic regulator PRMT5, and that Men1 inhibition leads to beta cell regeneration and amelioration of type 2 diabetes. Thus, in this proposal, how menin represses transcription of cell cycle-regulating genes, such as GLP-1-induced cyclin A, will be investigated. Second, the mechanisms underlying the interplay between menin and the GLP-1 pathway in controlling cyclin A transcription and beta cell proliferation will be elucidated. Third, the impact of Men1 inhibition on ameliorating T2D will be examined in T2D mouse models. These studies will likely unravel novel mechanisms in control of beta cell proliferation by the interplay between menin and the GLP-1 pathway through epigenetic regulation of gene transcription. The proposed studies may pave the way to developing novel and menin pathway-based strategies to treat T2D. PUBLIC HEALTH RELEVANCE: There are over 20 million patients with diagnosed or undiagnosed type 2 diabetes in the United States of America; in these patients there is an inadequate number of beta cells to control blood glucose. Our proposed studies likely unravel a new pathway, the menin pathway, in controlling beta cell proliferation, and this pathway could be modulated to ameliorate type 2 diabetes. These studies will likely pave the way to develop the next generation of new drugs to treat this widespread disease.

描述（由申请人提供）：需要足够数量的β细胞来产生足够量的胰岛素以维持正常血糖。增强 β 细胞增殖或再生可能是治疗 2 型糖尿病 (T2D) 的有效手段。编码核蛋白 menin 的多发性内分泌肿瘤 1 型基因 (Men1) 的突变通常会导致多个内分泌器官（例如胰岛）良性增生，但不会影响其他器官（例如肝脏）。我们的长期目标之一是了解 menin 如何调节 β 细胞增殖。尽管利用抑制 menin 来增强 β 细胞再生和改善糖尿病很有吸引力，但由于担心 menin 抑制可能产生潜在的致瘤作用，这一度被认为是有问题或不可行的。然而，最近快速的研究进展改变了这一观点。 Menin 在生理上受到抑制，可增加 β 细胞增殖并预防妊娠糖尿病。我们最近的研究结果表明，menin 与胰高血糖素样肽 1 (GLP-1) 信号通路相互作用，促进 β 细胞再生，从而调节基因转录。例如，menin 会抑制细胞周期蛋白 A 的表达，但 GLP-1 会增加细胞周期蛋白 A 的表达，从而将 menin 与 GLP-1 信号传导联系起来。 Menin 与 PRMT5 相互作用，PRMT5 是一种抑制基因转录的组蛋白精氨酸甲基转移酶。值得注意的是，Men1 切除不仅使小鼠对链脲佐菌素 (STZ) 诱导的高血糖产生抵抗力，而且还改善了 STZ 诱导的糖尿病小鼠中先前存在的高血糖。我们自上次提交以来的新结果还表明，急性 Men1 切除使高脂肪饮食喂养的小鼠中预先存在的葡萄糖不耐受正常化。这些发现强烈表明，抑制 menin 可能是增强 β 细胞再生和改善糖尿病的新方法。据推测，menin 通常通过抑制细胞周期调节因子的转录来抑制 β 细胞增殖，例如 GLP-1 诱导的细胞周期蛋白 A 与表观遗传调节因子 PRMT5 协同作用，Men1 抑制可导致 β 细胞再生并改善 2 型糖尿病。因此，在本提案中，将研究 menin 如何抑制细胞周期调节基因（例如 GLP-1 诱导的细胞周期蛋白 A）的转录。其次，将阐明 menin 和 GLP-1 通路在控制细胞周期蛋白 A 转录和 β 细胞增殖中相互作用的潜在机制。第三，将在 T2D 小鼠模型中检查 Men1 抑制对改善 T2D 的影响。这些研究可能会通过基因转录的表观遗传调控，通过 menin 和 GLP-1 通路之间的相互作用来揭示控制 β 细胞增殖的新机制。拟议的研究可能为开发新的基于 menin 途径的 T2D 治疗策略铺平道路。 公共卫生相关性：美国有超过 2000 万确诊或未确诊的 2 型糖尿病患者；这些患者的β细胞数量不足以控制血糖。我们提出的研究可能揭示了控制 β 细胞增殖的新途径，即 menin 途径，并且可以调节该途径来改善 2 型糖尿病。这些研究可能会为开发下一代新药来治疗这种广泛疾病铺平道路。