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.

肥胖症的患病率在美国正在迅速发展。结果，与肥胖相关的代谢疾病 这种赋予CVD风险增加，包括糖尿病，血脂异常和高血压正在流行 比例。肥胖症不良代谢后果的敏感性在人群中有很大差异： 适度的肥胖增加导致某些人严重代谢代谢，而其他人则导致 尽管肥胖严重，但仍保持正常的代谢特征。该项目的总体目标是确定 特定的遗传机制解释了代谢反应过多的变异性的特定遗传机制 并评估针对这些机制的药物的治疗潜力。该研究包括三个 互补策略：首先，我们将在大型多种族中对选定的候选基因进行测序 人口（达拉斯心脏研究），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相关联。我们的重点将放在两组基因上： 1）编码循环蛋白的基因，这些蛋白质在大脑，肝脏，脂肪组织之间携带代谢信号， 和肠道（“ metabokines”），以及2）编码选定转录调节分子的基因 响应代谢信号（“细胞代谢调节剂”）。这些研究中包括基因是 在项目1-3中进行了机械询问。其次，我们将使用全基因组方法作为公正 发现新基因和序列变体的方法，这些变体有助于个人间个体 代谢反应对肥胖症的差异。第三，我们将与项目4的调查人员合作4 ＆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 对肥胖症不良代谢后果的易感性遗传变异的机理基础。 这个雄心勃勃的跨学科计划利用了我们在仔细表型配对的既定优势 通过人类的综合遗传分析来表征以发现新基因和序列 导致代谢特征的变化。此外，我们建立了提供访问权限的合作 对于大型的前瞻性人群研究，遗传序列变异的影响可以严格 经过验证。这些合作以及我们合作者在项目中的补充专业知识 1-5极大地扩大了我们研究的科学范围，并提高了我们识别新治疗的潜力 预防和治疗肥胖的不良代谢后果的目标和方法。