The Regulation of Gene Expression via Epigenetic Mechanisms during Onset of Obesity, Type 2 Diabetes

 描述(申请人提供)：在过去的几十年里，肥胖和肥胖相关的2型糖尿病已经成为全球范围内的严重健康问题。自1990年以来，成年人和儿童的肥胖率都大幅上升。在如此短的时间内，人类的遗传编码不可能因进化而发生如此显著的变化。对肥胖/2型糖尿病等慢性复杂疾病的研究正在将重点从遗传致病因素转移到表观遗传和环境影响上。包括饮食和生活方式在内的环境因素可能通过影响人类基因组的表观遗传修饰而在肥胖/2型糖尿病的发生发展中发挥重要作用。最近的研究表明，循环脂肪酸与肥胖、胰岛素抵抗和肌肉细胞死亡有关。现在，关键的问题是，由脂肪酸诱导的脂肪细胞和肌肉细胞中的哪些实际因素是介导肥胖、胰岛素抵抗和肌肉细胞死亡的因素。每一个问题很可能都是由脂肪酸调节不止一个基因造成的。我们的初步数据表明，饱和脂肪酸和多不饱和脂肪酸都能诱导分化的脂肪细胞中的脂肪积聚，而饱和脂肪酸对脂肪细胞和肌肉细胞的影响不同。建议的项目从表观遗传学的角度系统地使用脂肪细胞和肌肉细胞来解决这些问题。目的1将确定脂肪细胞中脂肪积累和胰岛素抵抗所必需的基因。对脂肪积累至关重要的基因应该是由饱和脂肪酸和不饱和脂肪酸以相同方式调节的基因，因为这两种类型的脂肪酸都会在分化的脂肪细胞中引起显着的脂肪积累。由于饱和脂肪酸和多不饱和脂肪酸对分化脂肪细胞胰岛素抵抗的影响不同，与胰岛素抵抗相关的基因可能受到饱和脂肪酸和多不饱和脂肪酸的相反调控。目标2将确定调节细胞死亡和胰岛素抵抗所必需的基因 在肌肉细胞中。根据我们的初步数据，在肌肉细胞中，介导肌肉细胞死亡和胰岛素抵抗的基因应该以相反的方式受到饱和脂肪酸和多不饱和脂肪酸的调节，因为这两种脂肪酸对肌肉细胞死亡和胰岛素抵抗的影响不同。目标3将确定表观遗传修饰是否参与了目标1和2中确定的基因的表达。这一目标的研究将主要集中在甲基化和microRNAs上。该项目可能直接导致确定潜在的药物靶点。该项目还将为2名研究生和10名本科生提供体验生物医学研究的机会。

 DESCRIPTION (provided by applicant): During the last a few decades, obesity and obesity related type 2 diabetes have become serious health problems worldwide. Obesity among both adults and children has significantly increased since 1990. During such a short period of time, genetic coding of human beings cannot be changed so significantly by evolution. Studies in chronic complex disorders such as obesity/type 2 diabetes are shifting the emphasis from genetic causative factors to epigenetic and environmental effects. Environmental factors including diets and lifestyles may play an important role in development of obesity/type 2 diabetes by influencing the epigenetic modifications to the human genome. It has been demonstrated recently that circulating fatty acids are associated with adiposity, insulin resistance, and muscle cell death. Now, the key question is what actual factors in adipocytes and muscle cells induced by fatty acids are mediating adiposity, insulin resistance, and muscle cell death. It is very likely each of the problems may be a result of regulation of more than one gene by fatty acids. Our preliminary data indicated that both saturated fatty acids and polyunsaturated fatty acids induced lipid accumulation in differentiated adipocytes while saturated fatty acids differentially affected adipocytes and muscles cells. The proposed project systematically addresses these questions using both adipocytes and muscle cells from the aspect of epigenetics. Aim 1 will identify the genes that are essential for lipid accumulation and insulin resistance in adipocytes. The genes that are essential for lipid accumulation should be the genes that are regulated by saturated fatty acids and unsaturated fatty acids in the same manner since both types of fatty acids cause significant lipid accumulation in differentiated adipocytes. The genes that are related with insulin resistance in differentiated adipocytes should be regulated by saturated fatty acids and polyunsaturated fatty acids in opposite manners since the two types of fatty acids have different effects on insulin resistance in differentiated adipocytes. Aim 2 will identify the genes essential for mediating cell death and insulin resistance in muscle cells. The genes that are mediating muscle cell death and insulin resistance should be regulated by saturated fatty acids and polyunsaturated fatty acids in opposite manners in muscle cells since these two types of fatty acids have different effects on muscle cell death and insulin resistance in muscle cells according to our preliminary data. Aim 3 will determine if epigenetic modifications are involved in mediating expression of genes identified in Aim 1&2. Studies in this Aim will be mainly focused on methylation and microRNAs. This project may directly lead to identification of potential drug targets. This project will also provide opportuniies for 2 graduate and 10 undergraduate Hispanic students to experience biomedical research.