Virtual systemic identification of drug targets of obesity candidate genes

肥胖候选基因药物靶点的虚拟系统识别

• 批准号: 10639818
• 负责人: Yingchang Lu
• 金额: $ 81.51万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639818
• 关键词: Action Potentials; Adverse effects; Agonist; Amygdaloid structure; Anxiety; Behavior; Behavioral; Bipolar Disorder; Body Weight decreased; Body fat; Body mass index; Brain; Brain Stem; Candidate Disease Gene; Central Nervous System; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Desire for food; Digestion; Dopamine Antagonists; Drug Targeting; Drug usage; Eating; Electronic Health Record; Endocannabinoids; Energy Intake; Esthesia; FDA approved; Feeling suicidal; GLP-I receptor; Genes; Genetic; Genetic study; Health system; Human; Hypothalamic structure; In Vitro; Individual; Induced pluripotent stem cell derived neurons; Investigation; LEPR gene; Length; Leptin; Limbic System; Link; Major Depressive Disorder; Mendelian randomization; Mental Depression; Metabolism; Methodology; Molecular; Moods; Mutation; Neurites; Neurons; Neuropeptides; Nucleus Accumbens; Obesity; Obesity Epidemic; Obsessive-Compulsive Disorder; Participant; Pathogenicity; Pathway interactions; Patients; Peripheral; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Physical activity; Plasma; Prevention; Production; Proteins; Proteome; Reporting; Resources; Rewards; Risk Behaviors; Safety; Satiation; Smoking; Structure of nucleus infundibularis hypothalami; Therapeutic; Trans-Omics for Precision Medicine; Transcript; Veterans; Waist-Hip Ratio; Work; adult obesity; analog; antagonist; bariatric surgery; biobank; cardiometabolism; cohort; comorbidity; differentiation protocol; drinking; drug action; effective therapy; exome; exome sequencing; functional genomics; genetic resource; genetic signature; genome wide association study; induced pluripotent stem cell; innovation; insulin signaling; islet amyloid polypeptide; lipid biosynthesis; liraglutide; neural circuit; new therapeutic target; novel; obesity risk; obesity treatment; pharmacologic; phenome; programs; receptor; rimonabant; screening; stem cell differentiation; substance use; success; therapeutic target; trait; transcriptome; virtual

Over 40% of adults are obese in the US. Although reducing caloric intake and/or increasing physical activity can lead to weight loss in the short to medium term in some people, they lose efficacy in the long term. Bariatric surgeries are currently the most durable and effective treatment for obesity but substantial complications have been reported. Pharmaceutical options for treating obesity have been very limited and not efficacious. Anti- obesity medications generally target either central nervous system (CNS) pathways that regulate sensations of satiety and fullness, or peripheral modulators of digestion, metabolism and lipogenesis that result in only modest effects. One of the major challenges in developing anti-obesity medications is that our CNS (i.e., hypothalamus, brainstem, and limbic system), which regulates appetite and food intake, substantially overlaps with those that modulate mood, anxiety and behavior. Several CNS-acting drugs that have been developed to suppress appetite for weight loss have adverse behavioral effects. For example, Rimonabant (endocannabinoid receptor antagonist) and Ecopipam (dopamine receptor antagonist) precipitate severe depression and suicide ideations; and the recent FDA-approved MC4R agonist (Setmelanotide) for individuals carrying pathogenic mutations in POMC, PCSK1 or LEPR genes along the leptin-melanocortin pathway also incurs similar psychiatric effects in 26% patients. All of these highlight safety issues in targeting the CNS for appetite suppression. However, the recent success of glucagon-like peptide-1 receptor (GLP1R) agonists (Liraglutide, Semagglutide, Tirzepatide, etc.) and amylin analogs (Cagrilintide) in treating obesity without apparent CNS-related adverse effects demonstrates the proof of principle that targeting certain parts of our CNS for weight loss can be safe, i.e., targeting specific neural circuits primarily in the brainstem for GLP1R agonists and amylin analogs. It also indicates that a subset of obesity genes can be safely targeted pharmaceutically in the CNS. There has been tremendous progress in genetic studies of obesity and adiposity traits in the past 20 years, especially led by our Genetic Investigation of ANThropometric traits [GIANT] consortium, which has identified >1,700 adiposity loci. These efforts offer an unprecedented opportunity to identify novel drug targets to treat obesity, a field that urgently needs a paradigm shift. By leveraging comprehensive GWAS resources for adiposity, psychiatric traits and addictive risk behaviors, and rich phenome information across large-scale biobanks, we propose to integrate multi-layers of omics to identify obesity genes using whole-exome sequencing, transcriptome-wide and proteome-wide association analyses (Aim 1), predict pharmacological effects upon targeting obesity genes using drug-target Mendelian randomization analyses and gene-based phenome-wide association analyses (Aim 2), and screen neuronal effects of obesity drug target genes in iPSC-derived neurons with CRISPR-based functional genomics (Aim 3). Our work will identify novel obesity drug targets that are both efficacious and safe to fill in the critical unmet need of pharmaceutical therapy of obesity.

在美国，超过40％的成年人肥胖。尽管减少热量摄入和/或增加体育锻炼可以 在某些人的短期内导致体重减轻，从长远来看，他们会失去疗效。减肥 目前，手术是肥胖症的最耐用和有效的治疗方法 报道了。治疗肥胖症的药物选择非常有限且不有效。反对- 肥胖药物通常针对调节感觉的中枢神经系统（CNS）途径 消化，代谢和脂肪形成的饱腹感和饱腹感或外围调节剂仅导致适度 效果。开发抗肥胖药物的主要挑战之一是我们的中枢神经系统（即下丘脑， 调节食欲和食物摄入量的脑干和边缘系统）与那些人重叠 调节情绪，焦虑和行为。已经开发出来抑制食欲的几种CNS作用药物 为了减肥会产生不利的行为影响。例如，rimonabant（内源性大麻素受体 拮抗剂）和ecopipam（多巴胺受体拮抗剂）沉淀出严重的抑郁和自杀想法； 以及最近由FDA批准的MC4R激动剂（SetMelanotide），用于携带致病突变的个体 POMC，PCSK1或LEPR基因沿着瘦素 - 甲状腺皮质素途径在 26％的患者。所有这些突出了针对中枢神经系统抑制食欲的安全问题。但是， 胰高血糖素样肽-1受体（GLP1R）激动剂的最新成功（Liraglutide，semagglutide，tirzepatide， 等）和淀粉蛋白类似物（Cagrilintide）治疗肥胖症而没有明显的CNS相关不良反应 证明原则的证据，即将我们的中枢神经系统的某些部位靶向减肥可以是安全的，即 主要针对GLP1R激动剂和淀粉蛋白类似物的脑干中的特定神经回路。也是如此 表明肥胖基因的一部分可以在中枢神经系统中安全地靶向药物。有 在过去的20年中，肥胖和肥胖特征的遗传研究取得了巨大进步，尤其是由我们的领导 人体测量特征[巨人]联盟的遗传研究，该联盟已确定> 1,700个肥胖基因座。 这些努力提供了一个前所未有的机会来识别肥胖的新型药物目标，这一领域是 迫切需要范式转移。通过利用全面的GWAS资源来肥胖，精神科特征 以及大规模生物库中令人上瘾的风险行为以及丰富的现象信息，我们建议整合 使用全异位测序，整个转录组和 全蛋白质组的关联分析（AIM 1），可以预测使用使用肥胖基因的药理作用 药物目标孟德尔随机分析和基于基因的现象范围的关联分析（AIM 2），， 肥胖药物靶基因在具有CRISPR功能的IPSC衍生神经元中的筛选神经元作用 基因组学（目标3）。我们的工作将确定新颖的肥胖药物靶标，既有效又安全地填充 对肥胖症的药物治疗的临界需求。