Genetic Susceptibility to Adverse Metabolic Consequences of Obesity

肥胖不良代谢后果的遗传易感性

• 批准号: 7883541
• 负责人: JONATHAN Charles COHEN
• 金额: $ 73.83万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883541
• 关键词: Accounting; Adipose tissue; Animal Model; Body Weight; Brain; Candidate Disease Gene; Collaborations; Diabetes Mellitus; Dyslipidemias; Epidemic; Fatty Liver; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genotype; Glucose; Goals; Heart; Human; Hypertension; Individual; Individual Differences; Interdisciplinary Study; Intestines; Lead; Liver; Metabolic; Metabolic Diseases; Methods; Molecular Conformation; Morbid Obesity; Mus; Obesity; Outcome; Participant; Phenotype; Population; Population Study; Predisposition; Prevalence; Prevention approach; Proteins; Research Design; Research Personnel; Risk; Role; Scanning; Signal Transduction; Single Nucleotide Polymorphism; Therapeutic; United States; Variant; base; density; genetic analysis; genome wide association study; genome-wide; genome-wide analysis; in vivo; lipid metabolism; new therapeutic target; novel therapeutic intervention; population based; prevent; programs; prospective; response; trait

The prevalence of obesity is burgeoning in the United States. As a result, obesity-related metabolic disorders that confer increased CVD risk, including diabetes, dyslipidemia, and hypertension are reaching epidemic proportions. Susceptibility to the adverse metabolic consequences of obesity varies widely in the population: modest increases in adiposity lead to severe metabolic decompensation in some individuals, whereas others maintain a normal metabolic profile despite severe obesity. The overall goal of this project is to identify specific genetic mechanisms that account for the variability of metabolic responses to excess body weight and to evaluate the therapeutic potential of agents that target these mechanisms. The study includes three complementary strategies: First, we will sequence selected candidate genes in a large, multi-ethnic population (The Dallas Heart Study) in which each participant has undergone extensive metabolic characterization and relate the phenotypes to selected genotypes. Our focus will be on two groups of genes: 1) genes encoding circulating proteins that carry metabolic signals between the brain, liver, adipose tissue, and intestine ('metabokines'), and 2) genes encoding selected transcriptional regulatory molecules than respond to metabolic signals ('cellular metabolic regulators'). Included in these studies are genes being mechanistically interrogated in Projects 1-3. Second, we will use genome-wide methods as unbiased approaches toward the discovery of new genes and sequence variants that contribute to inter-individual differences in the metabolic responses to obesity. Third, we will collaborate with investigators in Projects 4 & 5 and perform detailed studies of glucose and lipid metabolism in both mice and humans to elucidate the mechanistic basis for genetic variation in susceptibility to the adverse metabolic consequences of obesity. This ambitious, interdisciplinary program leverages our established strengths in pairing careful phenotypic characterization with comprehensive genetic analyses in humans to discover new genes and sequence variations contributing to metabolic traits. In addition we have established collaborations that provide access to large, prospective population studies in which the effects of genetic sequence variants can be rigorously validated. These collaborations, together with the complementary expertise of our collaborators in Projects 1-5 greatly expand the scientific scope of our studies and increases our potential to identify new therapeutic targets and approaches to prevent and treat the adverse metabolic consequences of obesity.

在美国，肥胖症的患病率正在迅速上升。因此，肥胖相关的代谢紊乱 导致心血管疾病风险增加的疾病，包括糖尿病、血脂异常和高血压正在流行 比例。人群对肥胖不良代谢后果的易感性差异很大： 肥胖的适度增加会导致某些人严重的代谢失代偿，而另一些人 尽管严重肥胖，但仍保持正常的代谢特征。该项目的总体目标是确定 解释超重代谢反应变化的特定遗传机制 并评估针对这些机制的药物的治疗潜力。该研究包括三项 互补策略：首先，我们将在一个大的、多种族的群体中对选定的候选基因进行测序 人群（达拉斯心脏研究），其中每个参与者都经历了广泛的代谢 表征并将表型与选定的基因型联系起来。我们的重点将放在两组基因上： 1) 编码循环蛋白的基因，这些蛋白在大脑、肝脏、脂肪组织之间携带代谢信号， 和肠道（“代谢因子”），以及2）编码选定转录调节分子的基因 对代谢信号做出反应（“细胞代谢调节剂”）。这些研究中包括基因 在项目 1-3 中进行机械询问。其次，我们将使用全基因组方法作为公正的方法 发现有助于个体间相互作用的新基因和序列变异的方法 对肥胖的代谢反应存在差异。第三，我们将与项目 4 的研究人员合作 & 5并对小鼠和人类的葡萄糖和脂质代谢进行详细研究，以阐明 肥胖不良代谢后果易感性遗传变异的机制基础。 这个雄心勃勃的跨学科计划利用了我们在配对仔细表型方面的既定优势 通过全面的人类遗传分析进行表征，以发现新的基因和序列 影响代谢特征的变异。此外，我们还建立了合作关系，提供访问权限 大型前瞻性人群研究，其中基因序列变异的影响可以被严格地 已验证。这些合作以及我们项目合作者的互补专业知识 1-5 极大地扩展了我们研究的科学范围并增加了我们发现新疗法的潜力 预防和治疗肥胖不良代谢后果的目标和方法。