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: 7645157
• 负责人: JONATHAN Charles COHEN
• 金额: $ 74.58万
• 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/7645157
• 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.

肥胖症的流行在美国正在迅速发展。因此，肥胖相关的代谢紊乱 包括糖尿病、血脂异常和高血压在内的导致心血管疾病风险增加的疾病正在流行 比例。对肥胖不良代谢后果的易感性在人群中差异很大： 适度的肥胖增加会导致某些个体出现严重的代谢失代偿， 即使严重肥胖也能保持正常的代谢状况。该项目的总体目标是确定 解释体重过多代谢反应变异性的特定遗传机制 并评估靶向这些机制的药物的治疗潜力。该研究包括三个 互补策略：首先，我们将在一个大的，多种族的， 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 表征并将表型与所选基因型相关联。我们将重点关注两组基因： 1)编码循环蛋白质的基因，这些蛋白质在大脑、肝脏、脂肪组织、 和肠（“代谢因子”），和2）编码选择的转录调节分子的基因， 对代谢信号作出反应（“细胞代谢调节剂”）。这些研究中包括基因， 在项目1-3中机械地询问。其次，我们将使用全基因组方法作为无偏的 方法对发现新的基因和序列变异，有助于个体间 对肥胖的代谢反应的差异。第三，我们将与项目4的调查人员合作， 和5，并在小鼠和人类中进行葡萄糖和脂质代谢的详细研究，以阐明 遗传变异对肥胖不良代谢后果的易感性的机制基础。 这个雄心勃勃的跨学科计划利用我们在配对仔细的表型 在人类中进行全面的遗传分析，以发现新的基因和序列 导致代谢特征的变异。此外，我们还建立了合作关系，提供访问权限 到大规模的前瞻性人群研究，其中基因序列变异的影响可以被严格地 验证.这些合作，以及我们在项目合作者的互补专业知识， 1-5大大扩展了我们研究的科学范围，并增加了我们发现新治疗方法的潜力 预防和治疗肥胖症的不良代谢后果的目标和方法。