From Obesity GWAS to therapeutic targets

项目摘要/摘要 肥胖会增加患2型糖尿病、心脏病、多种癌症、高血压、 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， 肥胖被发现有40%-70%的遗传率，这表明有很强的遗传病因。长期的 我们研究的目标是确定基因变异如何使人类容易肥胖，以及 治疗方面的影响是针对这种情况的。 为了寻找与肥胖相关的常见遗传变异，大量全基因组关联研究(GWAS) 都已经完成了。超过500个基因座被发现与体重指数(BMI)增加有关，所有这些 其中存在于基因组的非编码区。然而，在勾勒出 因果SNPs和了解它们实际导致肥胖的机制。 在这个提案中，我们探索了肥胖相关SNPs影响调控区域的假设 活跃在神经元亚群中，参与食物摄入量和体重的调节。 使用我们最近通过Ahituv和Ahituv之间的合作开创的最先进的方法 和Vaisse实验室，我们建议： -扩展和完善与身体有关的下丘脑神经元亚群的调控格局 体重调节以确定重叠肥胖GWA单核苷酸的候选调节元件 多态(SNPs)。 -在小鼠中使用CRISPR失活(CRISPRi)直接测试调节元件的功能作用 包括与肥胖相关的SNPs。 -在小鼠中使用CRISPR激活(CRISPRa)来测试识别的活动调节的治疗潜力 目标监管区域。 总而言之，我们的工作不仅将提供与肥胖相关的神经元亚型的调节图，而且 从功能上描述这些区域，并展示其治疗潜力。

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.