From Obesity GWAS to therapeutic targets

项目总结/摘要 肥胖会增加患2型糖尿病、心脏病发作、多种癌症、高血压的风险， 中风，估计很快就会成为美国的主要死亡原因。通过双胞胎和家庭研究， 已经发现肥胖症具有40-70%的遗传率，这表明肥胖症有很强的遗传病因。长期 我们研究的目的是确定遗传变异如何使人类易患肥胖症， 治疗的意义在于这种情况。 为了找到与肥胖相关的常见遗传变异，许多全基因组关联研究（GWAS） 已经执行。已经发现超过500个位点与体重指数（BMI）增加有关，所有 它们位于基因组的非编码区。然而，在概述 因果SNPs和了解它们实际上导致肥胖的机制。 在这项提议中，我们探讨了肥胖相关的SNP影响调节区域的假设， 在涉及食物摄入和体重调节的神经元亚群中具有活性。 使用我们最近通过与Ahituv合作开创的最先进的方法， 和Vaisse实验室，我们建议： - 扩展和完善下丘脑神经元亚群的调节景观涉及身体 体重调节以鉴定与肥胖重叠的候选调节元件GWAS单核苷酸 多态性（SNP）。 - 在小鼠中使用CRISPR失活（CRISPRi）来直接测试调控元件的功能作用， 包括肥胖相关的SNP。 - 在小鼠中使用CRISPR活化（CRISPRa）来测试鉴定的CRISPR活性调节的治疗潜力。 目标监管区域。 结合起来，我们的工作不仅将提供与肥胖相关的神经元亚型的调控图谱， 在功能上表征这些区域并显示其治疗潜力。

Project Summary/Abstract Obesity leads to an increased risk for type 2 diabetes, heart attack, many types of cancer, hypertension, stroke, and is estimated to soon be the leading cause of death in the US. Through twin and family studies, obesity has been found to have a 40-70% heritability rate, pointing to a strong genetic etiology. The long-term objective of our studies is to determine how genetic variation predisposes humans to obesity and what the therapeutic implications are for this condition. To find common genetic variants associated with obesity, numerous genome-wide association studies (GWAS) have been performed. Over 500 loci have been found to associate with increased body weight index (BMI), all of which reside in noncoding regions of the genome . However, little progress has been made in outlining the causal SNPs and understanding the mechanisms by which they actually cause obesity. In this proposal, we explore the hypothesis that obesity-associated SNPs affect regulatory regions that are active in neuronal sub-population implicated in the regulation of food intake and body weight. Using state-of-the-art approaches that we have recently pioneered through collaborations between the Ahituv and Vaisse laboratories we propose to: - Extend and refine the regulatory landscape of hypothalamic neuronal subpopulations implicated in body weight regulation to identify candidate regulatory elements overlapping obesity GWAS single nucleotide polymorphisms (SNPs). - Use CRISPR inactivation (CRISPRi) in mice to directly test the functional role of regulatory elements that encompass obesity-associated SNPs. - Use CRISPR activation (CRISPRa) in mice to test the therapeutic potential of activity modulation of identified target regulatory regions. Combined, our work will not only provide a regulatory map of neuronal subtypes associated obesity, but also functionally characterize these regions and show their therapeutic potential.