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

肥胖、2 型糖尿病发病期间通过表观遗传机制调节基因表达

• 批准号: 9270051
• 负责人: Yi Li
• 金额: $ 10.32万
• 依托单位: TEXAS A&M UNIVERSITY-KINGSVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-05 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270051
• 关键词: 3T3-L1 Cells; Address; Adipocytes; Adipose tissue; Adult; Affect; Area; Biomedical Research; Cell Death; Cell Differentiation process; Cells; Cessation of life; Child; Chronic; Complex; DNA Methylation; DNA Microarray Chip; Data; Development; Diet; Disease; Drug Targeting; Environmental Risk Factor; Epigenetic Process; Evolution; Fatty Acids; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Code; Genomic DNA; Health; Hispanic Graduate Student; Hispanics; Human; Human Genome; Hyperlipidemia; Individual; Infiltration; Insulin Resistance; Lead; Life Style; Linoleic Acids; Lipids; Mediating; Methylation; MicroRNAs; Modification; Mus; Muscle; Muscle Cells; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Palmitic Acids; Patients; Play; Polyunsaturated Fatty Acids; Regulation; Research; Research Project Grants; Role; Saturated Fatty Acids; Small Interfering RNA; Students; Techniques; Time; Tissues; Underrepresented Students; Unsaturated Fatty Acids; adipocyte differentiation; epigenetic regulation; experience; public health relevance; targeted treatment; undergraduate student

 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.

 描述（由申请人提供）：在过去的几十年中，肥胖和肥胖相关的2型糖尿病已成为全球严重的健康问题。自1990年以来，成人和儿童的肥胖症都有显著增加。在如此短的时间内，人类的遗传编码不可能通过进化而发生如此重大的变化。对慢性复杂疾病（如肥胖/2型糖尿病）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。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在肥胖/2型糖尿病的发展中发挥重要作用。最近已经证明，循环脂肪酸与肥胖、胰岛素抵抗和肌细胞死亡有关。现在，关键问题是脂肪酸诱导的脂肪细胞和肌肉细胞中的哪些实际因素介导了肥胖、胰岛素抵抗和肌肉细胞死亡。很可能每一个问题都可能是脂肪酸调节多个基因的结果。我们的初步数据表明，饱和脂肪酸和多不饱和脂肪酸诱导分化的脂肪细胞中的脂质积累，而饱和脂肪酸差异影响脂肪细胞和肌肉细胞。该项目从表观遗传学的角度，利用脂肪细胞和肌肉细胞系统地解决了这些问题。目的1将确定脂肪细胞中脂质积累和胰岛素抵抗所必需的基因。对于脂质积累必不可少的基因应该是以相同方式由饱和脂肪酸和不饱和脂肪酸调节的基因，因为两种类型的脂肪酸在分化的脂肪细胞中引起显著的脂质积累。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，因此，与分化脂肪细胞胰岛素抵抗相关的基因可能受到这两种脂肪酸相反的调控。目的2将确定介导细胞死亡和胰岛素抵抗的基因 在肌肉细胞中。根据我们的初步数据，在肌细胞中，介导肌细胞死亡和胰岛素抵抗的基因应该由饱和脂肪酸和多不饱和脂肪酸以相反的方式调节，因为这两种类型的脂肪酸对肌细胞死亡和肌细胞中的胰岛素抵抗具有不同的影响。目标3将确定表观遗传修饰是否参与介导目标1&2中鉴定的基因的表达。这方面的研究将主要集中在甲基化和microRNA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名本科西班牙裔学生提供体验生物医学研究的机会。