From Obesity GWAS to therapeutic targets

从肥胖 GWAS 到治疗目标

• 批准号: 10642716
• 负责人: Nadav Ahituv
• 金额: $ 70.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642716
• 关键词: ATAC-seq; Address; Affect; Anatomy; Biological Assay; Body Weight; CRISPR-mediated transcriptional activation; Cause of Death; Central Nervous System; ChIP-seq; Chromosome Mapping; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Disease; Eating; Elements; Environment; Family Study; Food Intake Regulation; Gene Expression; Genes; Genetic Predisposition to Disease; Genetic Variation; Genome; Genomics; Harvest; Heart Diseases; Heritability; High Fat Diet; Homeostasis; Human; Human Genome; Hypertension; Hypothalamic structure; Injections; Knowledge; Laboratories; Link; Malignant Neoplasms; Maps; Metabolic; Modeling; Mus; Myocardial Infarction; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acid Regulatory Sequences; Obesity; Phenotype; Population; Protocols documentation; Public Health; Recombinant adeno-associated virus (rAAV); Regulation; Regulator Genes; Regulatory Element; Resources; Risk; Role; Single Nucleotide Polymorphism; Stroke; Technology; Testing; Therapeutic; Twin Studies; Untranslated RNA; Variant; Weight; Weight Gain; Work; cancer type; candidate identification; differential expression; genetic variant; genome wide association study; in vivo; indexing; obesity treatment; therapeutic evaluation; therapeutic target; transcriptome; transcriptome sequencing

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.

项目总结/文摘