Probing genetics and biology of human circadian function

探索人类昼夜节律功能的遗传学和生物学

• 批准号: 9750844
• 负责人: LOUIS J. PTACEK
• 金额: $ 57.62万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750844
• 关键词: Advanced Sleep Phase Syndrome; Affect; Age; Aging; Algorithms; Animal Model; Area; Asthma; Attention; Bacterial Artificial Chromosomes; Behavior; Behavioral; Behavioral Genetics; Biology; Blood specimen; Candidate Disease Gene; Cardiovascular Diseases; Childhood; Circadian Dysregulation; Circadian Rhythms; Clinical; Clinical Data; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collection; Complex; DNA; Development; Diagnosis; Diet Habits; Disease; Family; Gene Mutation; Genes; Genetic; Genetic study; Health; Health Personnel; Hour; Human; Human Biology; Impairment; In Vitro; Individual; Investigation; Jet Lag Syndrome; Knowledge; Lead; Learning Disorders; Life; Light; Link; Malignant Neoplasms; Maps; Mental disorders; Metabolic; Metabolic syndrome; Molecular; Mutation; Nature; Nuclear; Organism; Pathway interactions; Pattern; Periodicity; Pharmacology; Phase; Phenotype; Physiological; Physiological Processes; Physiology; Planet Earth; Police officer; Population; Proteins; Psyche structure; Public Domains; RNA Splicing; Regulatory Pathway; Repressor Proteins; Resources; Role; Sampling; Schedule; Series; Sleep; Sleep Disorders; Sleep Wake Cycle; Technology; Time; Transgenic Organisms; Travel; Variant; Work; alertness; autosomal dominant trait; base; causal variant; circadian; circadian pacemaker; circadian regulation; clinical phenotype; exome sequencing; family genetics; genetic linkage; genetic pedigree; genetic variant; human disease; human model; improved; in vivo; insight; mouse model; next generation sequencing; novel; proband; sleep behavior; sleep quality; success; young adult

ABSTRACT On planet earth, organisms have evolved mechanisms to synchronize metabolic and physiological functions with the ~24 hour light/dark cycle. Interestingly, many human diseases have associations with the circadian day. When traveling across time zones, our sleep-wake patterns, mental alertness, eating habits and many other physiological processes temporarily suffer the consequences of being “out of phase” until we adjust to the new time zone. In addition, a significant portion of the population works the ‘graveyard’ shift, including health care workers, police officers, truck drivers and factory workers. Recent studies have linked disruption of the circadian clock with numerous ailments, including: asthma, cancer, metabolic syndrome, cardiovascular diseases, psychiatric diseases, and learning disorders. Tremendous knowledge has come from studying the genetic and molecular basis of circadian rhythms in model organisms. Despite the importance of the circadian clock to all aspects of our physiology and behavior, the opportunity to probe the human circadian clock only became possible with the recognition of Mendelian circadian variants in people (familial advanced sleep-phase, FASP). We characterized FASP, collected many families, and mapped and cloned the first FASP genes. We went on to identify a total of 6 FASP genes and have generated animal models of all of them. Still, a large majority of FASP families do not have mutations in the known clock genes. In this proposal, we outline a plan to continue collecting additional families (Aim 1), to perform whole exome sequencing in probands from >50 ‘unexplained’ FASP families, and to sift among the variants to identify novel circadian rhythm/FASP genes/mutations (Aim 2). Finally, since the first 1-2 years will be focused on identifying novel FASP genes, we propose to perform in vitro and in vivo studies of a human FASP mutation in the TIMELESS gene (Aim 3). Parallel studies in humans and mouse models will synergize in dissecting understanding of FASP in humans and exploring the similarities and differences between our circadian clocks vs. those of other organisms. Studying the molecular mechanism of human circadian rhythmicity will have an enormous impact on our understanding of human health & disease. It should also lead to new strategies for pharmacological manipulation of the human clock to improve the treatment of jet-lag, various clock-related sleep and psychiatric disorders, as well as other human diseases. Understanding of the human clock genes and mutations will enable development of better therapies for ASPS of aging, jet lag, and other sleep disorders.

摘要