Link of Beta Cell Proliferation and Type 2 Diabetes to Epigenetic Regulation

描述(由申请人提供)：需要足够数量的β细胞来产生足够数量的胰岛素以维持正常血糖。促进胰岛β细胞的增殖或再生是治疗2型糖尿病的有效手段。编码核蛋白Menin的多发性内分泌肿瘤1型基因(MEN1)的突变通常会导致几个内分泌器官的良性增生，如胰岛，但不会影响其他器官，如肝脏。我们的长期目标之一是了解薄荷素是如何调控β细胞增殖的。尽管利用抑制薄荷素来促进β细胞再生和改善糖尿病是有吸引力的，但这曾经被认为是有问题的或不可行的，因为担心抑制薄荷素的潜在致癌作用。然而，最近快速的研究进展改变了这种观点。梅宁在生理上受到抑制，以促进β细胞增殖和预防妊娠期糖尿病。我们最近的发现表明，薄荷素与促进β细胞再生的胰升糖素样肽1(GLP-1)信号通路相互作用，调节基因转录。例如，薄荷素抑制细胞周期蛋白A的表达，而GLP-1则促进细胞周期蛋白A的表达，从而将薄荷素与GLP-1信号联系起来。梅宁与组蛋白精氨酸甲基转移酶PRMT5相互作用，组蛋白精氨酸甲基转移酶抑制基因转录。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诱导的糖尿病小鼠原有的高血糖。自上次提交以来，我们的新结果也表明，急性MEN1切除可以使高脂饮食喂养的小鼠原有的葡萄糖耐量正常化。这些发现有力地表明，抑制薄荷素可能是一种促进β细胞再生和改善糖尿病的新方法。假设薄荷素通常通过抑制细胞周期调节因子的转录来抑制β细胞的增殖，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，抑制MEN1导致β细胞再生和2型糖尿病的改善。因此，在这项提案中，将研究薄荷素如何抑制细胞周期调节基因的转录，如GLP-1诱导的细胞周期蛋白A。其次，将阐明脑膜素和GLP-1途径在控制细胞周期蛋白A转录和β细胞增殖中相互作用的机制。第三，将在T2D小鼠模型中检验抑制MEN1对改善T2D的影响。这些研究可能会揭示新的机制，通过脑膜素和GLP-1途径之间的相互作用，通过基因转录的表观遗传调控来控制β细胞的增殖。所提出的研究可能为开发基于薄荷素途径的治疗T2D的新策略铺平道路。 公共卫生相关性：美利坚合众国有2000多万确诊或未确诊的2型糖尿病患者；在这些患者中，β细胞数量不足，无法控制血糖。我们提出的研究可能揭开了一条新的途径，即薄荷素途径，控制β细胞的增殖，这一途径可能被调节以改善2型糖尿病。这些研究可能会为开发下一代治疗这种广泛传播的疾病的新药铺平道路。

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.