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

项目总结/摘要 昼夜节律，我们的24个日常生物节律，控制着我们几乎所有的基本生物功能， 对环境敏感。将环境和药物干预引导到受干扰的 昼夜节律具有治疗许多疾病的未开发潜力，包括癌症、精神疾病和 心脏代谢疾病然而，我们首先需要了解参与的分子机制， 昼夜节律，特别是那些将人类昼夜节律系统与下游疾病联系起来的昼夜节律。人类 遗传学可以为解决这一知识差距提供重要的见解。 这项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 预防性临床护理和治疗，采用多方面和创新的方法。我的研究项目 从基因发现到功能跟踪，再到翻译应用，目标是未来五年 1）使用现有的生物库来识别具有极端昼夜行为的个体，以进行罕见变异研究 导致识别参与昼夜节律的基因和途径; 2）开发可扩展的人类 昼夜节律表型分析方法，用于详细研究大规模人群的昼夜节律行为 良好的动力遗传研究;和3）创建新的昼夜功能后续细胞测定与 在各种环境和遗传背景下询问基因敲除的影响的潜力， 将这种新的功能性筛选与果蝇昼夜节律行为的行为测定配对。 我很有能力领导这个研究项目，因为我的背景是人类遗传学， 昼夜节律和细胞筛选，用于下游功能测定，并具有成功的证明记录。 同时，我有现在和未来的合作者定位，以贡献他们的专业知识，这一研究计划， 在人口遗传学研究，人类昼夜节律表型和细胞昼夜节律方面具有特定的专业知识， 测定。 预期的结果是：1）基因，途径和细胞类型，有助于昼夜生理学，特别是 核心分子生物钟以外的机制; 2）生物钟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 用于广泛研究和护理的研究和临床用途的昼夜节律表型;以及4）新颖的 用于昼夜节律紊乱和因果关联紊乱的药物靶标。这些发现将使 为罕见的昼夜节律紊乱开发新的治疗方法，并增加我们的理解 的基本机制，昼夜节律生物学在人类，并最终阐明如何昼夜节律 失调易患更常见的相关神经精神和心脏代谢疾病。

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.