Genetics of human circadian rhythms: using sequencing, novel phenotyping methods, and functional assays to move towards a deeper understanding of circadian mechanisms

人类昼夜节律的遗传学：利用测序、新颖的表型分析方法和功能分析来更深入地了解昼夜节律机制

• 批准号: 10707160
• 负责人: Jacqueline Marie Lane
• 金额: $ 44.75万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707160
• 关键词: Address; Behavior; Behavioral Assay; Biological Assay; Biological Process; Biological Rhythm; Biology; Cardiometabolic Disease; Caring; Cellular Assay; Circadian Dysregulation; Circadian Rhythm Disorder; Circadian Rhythms; Clinical; Clinical Treatment; Development; Disease; Drosophila genus; Environment; Future; Genes; Genetic; Genetic Population Study; Genetic study; Goals; Health; Human; Human Genetics; Individual; Intervention; Investigation; Knowledge; Lead; Link; Malignant Neoplasms; Methods; Molecular; Outcome; Pathway interactions; Pharmacologic Substance; Phenotype; Physiology; Population; Positioning Attribute; Research; Role; System; Vision; Workplace; biobank; cell type; circadian; circadian biology; circadian pacemaker; clinical care; educational atmosphere; experience; follow-up; innovation; insight; knockout gene; neuropsychiatric disorder; novel; novel therapeutics; pharmacologic; programs; rare variant; risk prediction; risk stratification; success; tool; translational applications

Project Summary/Abstract Circadian rhythms, our 24 daily biological rhythms, control nearly all our basic biological functions and are sensitive to the environment. Directing both environmental and pharmacological interventions at disrupted circadian rhythms has untapped potential to treat many conditions including cancer, psychiatric conditions, and cardiometabolic disorders. We first need, however, to understand the molecular mechanisms involved in circadian rhythms, particularly those linking the human circadian system to downstream disorders. Human genetics can provide insights important to address this gap in knowledge. The overall vision of this research program is understanding the underlying mechanisms of the human circadian system and its role in human health leading to integration of the temporal axis of our biology into preventative clinical care and treatment using a multifaceted and innovative approach. My research program spans from genetic discovery to functional follow-up to translational applications with the goals for the next five years to 1) use existing biobanks to identify individuals with extreme circadian behavior for rare variant studies resulting in identification of genes and pathways involved in circadian rhythms; 2) develop scalable human circadian phenotyping methods to enable detailed investigations of circadian behavior in large-scale populations well-powered for genetic studies; and 3) create novel circadian function follow-up cellular assays with the potential to interrogate the impact of gene knock out in a variety of environmental and genetic backgrounds and pair this novel functional screen with drosophila behavioral assays of circadian behavior. I am well-positioned to lead this research program as my background is in human genetics with experience in circadian rhythms and cellular screens for downstream functional assays with a proven-track record of success. As well, I have current and future collaborators positioned to contribute their expertise to this research program, with specific expertise in population genetic studies, circadian phenotyping in humans, and cellular circadian assays. Expected outcomes are: 1) genes, pathways, and cell types that contribute to circadian physiology particularly mechanisms beyond the core molecular circadian clock; 2) Tools for circadian risk prediction and stratification with utility in the workplace, educational environments, and clinical care; 3) Easy to implement and dynamic circadian phenotyping for research and clinical use across a broad range of study and care; and 4) Novel pharmaceutical targets for circadian rhythm disorders and causally linked disorders. These findings will allow for the development of novel therapeutics for rare circadian rhythms disorders and increase our understanding of the basic mechanisms of circadian biology in humans, and ultimately shed light on how circadian rhythm dysregulation predisposes to more common associated neuropsychiatric and cardiometabolic diseases.

项目摘要/摘要 昼夜节律，我们每天的24个生物节律，控制着我们几乎所有的基本生物功能，并且是 对环境很敏感。将环境和药物干预引导到Disrupt 昼夜节律具有尚未开发的治疗多种疾病的潜力，包括癌症、精神疾病和 心脏新陈代谢障碍。然而，我们首先需要了解涉及到的分子机制 昼夜节律，尤其是那些将人类的昼夜节律系统与下游紊乱联系起来的节律。人类 遗传学可以提供解决这一知识差距的重要见解。 这个研究计划的总体愿景是了解人类的潜在机制 昼夜节律系统及其在人类健康中的作用导致我们生物学的时间轴整合到 使用多方面和创新的方法进行预防性临床护理和治疗。我的研究计划 从基因发现到翻译应用的功能跟踪，目标是未来五年 年1)使用现有的生物库识别具有极端昼夜行为的个体，以进行罕见的变异研究 导致识别与昼夜节律有关的基因和途径；2)开发可伸缩的人类 能够对大规模人群的昼夜行为进行详细研究的昼夜节律表型方法 为遗传学研究提供了强大的动力；以及3)利用 在各种环境和遗传背景中询问基因敲除的影响的可能性 将这一新的功能屏幕与果蝇昼夜行为的行为分析配对。 我很适合领导这个研究项目，因为我的背景是人类遗传学，有 用于下游功能分析的昼夜节律和细胞筛查，以及经过验证的成功记录。 此外，我现在和未来的合作者都准备为这个研究项目贡献他们的专业知识， 在种群遗传学研究、人类昼夜节律表型和细胞昼夜节律方面具有特殊专长 化验。 预期的结果是：1)对昼夜节律生理学特别有贡献的基因、途径和细胞类型 核心分子昼夜节律时钟之外的机制；2)昼夜节律风险预测和分层工具 在工作场所、教育环境和临床护理中具有实用性；3)易于实施和动态 在广泛的研究和护理中用于研究和临床的昼夜节律表型；以及4)新颖 治疗昼夜节律紊乱和因果关联紊乱的药物靶标。这些发现将使 为开发治疗罕见昼夜节律紊乱的新疗法并增加我们的认识 人类昼夜节律的基本机制，并最终阐明了昼夜节律如何 调节失调易导致更常见的相关神经、精神和心脏代谢疾病。