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）：产生足够量的胰岛素以维持正常血糖的数量需要足够数量的β细胞。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。编码核蛋白梅宁的多内分泌肿瘤1型基因（MEN1）中的突变通常会导致几种内分泌器官（例如胰岛）的良性增生，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细胞的扩散。尽管它可以吸引抑制Menin来增强β细胞再生并改善糖尿病，但由于担心梅宁抑制作用的潜在肿瘤效应，这曾经被认为是有问题或不可行的。但是，最近和快速的研究进展改变了这一观点。梅宁在生理上受到抑制，以增加β细胞增殖并预防妊娠糖尿病。我们最近的发现表明，Menin与胰高血糖素样肽1（GLP-1）信号通路的相互作用促进了β细胞再生以调节基因转录。例如，Menin抑制，但是GLP-1会增加细胞周期蛋白A表达，将Menin与GLP-1信号联系起来。 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切除不仅会使抗链霉菌素（STZ）诱导的高血糖的小鼠可改善STZ诱导的糖尿病小鼠中预先存在的高血糖。自上次提交以来，我们的新结果还表明，急性MEN1切除在高脂饮食喂养的小鼠中标准化了葡萄糖不耐症。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。假设Menin通常通过抑制细胞周期调节剂的转录来抑制β细胞的增殖，例如 GLP-1诱导的细胞周期蛋白A，与表观遗传调节剂PRMT5一致，MEN1抑制会导致β细胞再生和改善2型糖尿病。因此，在此提案中，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与GLP-1途径之间相互作用的机制控制细胞周期蛋白A转录和β细胞增殖。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Menin与GLP-1途径之间的相互作用通过基因转录的表观调节来控制β细胞增殖的新型机制。拟议的研究可能为制定基于新颖和Menin途径的治疗T2D的策略铺平了道路。 公共卫生相关性：美国有超过2000万患有被诊断或未诊断的2型糖尿病的患者；在这些患者中，无法控制血糖的β细胞数量不足。我们提出的研究可能会在控制β细胞增殖方面揭示新的途径，即Menin途径，并且该途径可以调节以改善2型糖尿病。这些研究可能会为开发下一代新药以治疗这种广泛的疾病铺平道路。