Telomere-based Epigenetic Reprogramming of Adipocyte Progenitor Cells inInsulin Resistance

7.项目摘要/摘要 美国退伍军人中2型糖尿病及相关心血管疾病的患病率是前者的三倍 与普通人群相比更高。这种差异在一定程度上是由于老年人年龄偏高造成的 退伍军人群体。目前，美国3000万2型糖尿病患者中有近一半 各州都有60年以上的历史。衰老是2型糖尿病的重要危险因素，并与 伴随着胰岛素敏感性的下降。生物体衰老所涉及的机制之一是缩短 染色体末端的端粒。这些保护性的核蛋白复合体由 端粒酶和防止再生组织重塑过程中的复制衰老。虽然端粒 缩短与2型糖尿病的风险增加有关，这是年龄和年龄之间的一种机械关系。 诱导的端粒磨损和胰岛素抵抗从未出现过。我们已经确认了生理上的 而遗传端粒磨损会导致胰岛素抵抗，并因复制而阻碍脂肪生成 衰老，肌肉和肝脏中异位脂肪沉积。端粒磨损改变细胞增殖能力 通过对脂肪细胞前体细胞的重新编程产生抑制性染色质修饰 哺乳动物SWI/SNF(BAF)染色质重塑复合体。提出了两个具体的目标来探索 这些发现的意义，并检验端粒磨损导致胰岛素抵抗的假设 通过在脂肪细胞前体细胞中的染色质沉默。在具体目标1中，我们将确定 脂肪细胞前体细胞端粒长度改变对脂肪组织再生和胰岛素的影响 抵抗。在具体目标2中，我们将利用细胞和分子方法的组合来确定 端粒磨损引起的表观遗传学重编程是否会导致脂肪组织前体细胞功能障碍。 最终，这些研究的结果不仅将端粒磨损描述为染色质修饰物 脂肪细胞前体细胞功能障碍也提供了新的机制基础 衰老与2型糖尿病的关系。

7. Project Summary/Abstract The prevalence of type 2 diabetes and associated cardiovascular disease among U.S. Veterans is three-fold higher compared to the general population. This disparity has been attributed in part to the advanced age of the Veteran population. Currently, nearly half of the 30 million patients with type 2 diabetes in the United States are older than 60 years. Aging constitutes an important risk factor for type 2 diabetes and is associated with a decline in insulin sensitivity. One of the mechanisms implicated in organismal aging is the shortening of telomeres at the ends of chromosomes. These protective nucleoprotein complexes are maintained by telomerase and prevent replicative senescence during regenerative tissue remodeling. Although telomere shortening is associated with an increased risk for type 2 diabetes, a mechanistic relationship between age- induced telomere attrition and insulin resistance has never been shown. We have identified that physiological and genetic telomere attrition results in insulin resistance, impaired adipogenesis due to replicative senescence, and ectopic lipid deposition in muscle and liver. Telomere attrition alters the proliferative capacity of adipocyte progenitor cells and generates repressive chromatin modifications by reprogramming of the mammalian SWI/SNF (BAF) chromatin-remodeling complex. Two specific aims are proposed to explore the significance of these findings and to test the hypothesis that telomere attrition induces insulin resistance through chromatin silencing in adipocyte progenitor cells. In Specific Aim 1 we will determine whether alterations in telomere lengths of adipocyte progenitor cells influence adipose tissue regeneration and insulin resistance. In Specific Aim 2 we will utilize a combination of cellular and molecular approaches to determine whether epigenetic reprogramming by telomere attrition induces adipose tissue progenitor cell dysfunction. Ultimately, the results of these studies will not only characterize telomere attrition as a chromatin modifier of adipocyte progenitor cell dysfunction but also provide novel insights into the mechanistic basis for the association between aging and type 2 diabetes.