Probing genetics and biology of human sleep homeostasis

探索人类睡眠稳态的遗传学和生物学

基本信息

批准号：
10452632
负责人：
LOUIS J. PTACEK
金额：
$ 66.62万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10452632
关键词：
ADRB1 gene Affect Alleles American Biological Biology Brain Candidate Disease Gene Cessation of life Chronic Code Collection DNA DNA Databases Databases Detection Drosophila genus Electroencephalography Epidemiology Family Family member Feeling GRM1 gene Gene Mutation Genes Genetic Genome Grant Health Homeostasis Hour Human Human Biology Immunity Impairment In Vitro Individual Induced Mutation Introns Investments Lead Life Maintenance Massive Parallel Sequencing Metabolism Minority Molecular Morbidity - disease rate Mus Mutation Nucleic Acid Regulatory Sequences Open Reading Frames Pathway interactions Patient Self-Report Persons Pharmaceutical Preparations Phenotype Physicians Population Proteins Regulation Reporting Resources Rest Risk Role Sampling Sleep Sleep Deprivation Sleep Disorders Stream Surveys Technology Temperature Translating United States National Institutes of Health Variant Well in self Work circadian clinical database exome exome sequencing genome sequencing human subject improved in vivo interest mortality mouse model novel proband psychosocial sleep behavior sleep pattern sleep quality sleep quantity sleep regulation trait whole genome

ADRB1 gene Affect Alleles American Biological Biology Brain Candidate Disease Gene Cessation of life Chronic Code Collection DNA DNA Databases Databases Detection Drosophila genus Electroencephalography Epidemiology Family Family member Feeling GRM1 gene Gene Mutation Genes Genetic Genome Grant Health Homeostasis Hour Human Human Biology Immunity Impairment In Vitro Individual Induced Mutation Introns Investments Lead Life Maintenance Massive Parallel Sequencing Metabolism Minority Molecular Morbidity - disease rate Mus Mutation Nucleic Acid Regulatory Sequences Open Reading Frames Pathway interactions Patient Self-Report Persons Pharmaceutical Preparations Phenotype Physicians Population Proteins Regulation Reporting Resources Rest Risk Role Sampling Sleep Sleep Deprivation Sleep Disorders Stream Surveys Technology Temperature Translating United States National Institutes of Health Variant Well in self Work circadian clinical database exome exome sequencing genome sequencing human subject improved in vivo interest mortality mouse model novel proband psychosocial sleep behavior sleep pattern sleep quality sleep quantity sleep regulation trait whole genome

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项目摘要

Project Summary Familial Natural Short Sleep (FNSS) is a rare Mendelian form of sleep where affected individuals have a lifelong requirement for sleep that is significantly less than the average person. These people often sleep 4-6 hours per night yet report feeling well-rested. In 2009, we reported the first human FNSS trait, identification of the causative gene/mutation. and characterization of a similarly short sleep phenotype in modeled mice (and a corresponding rest-activity phenotype in Drosophila). We have since identified over 90 FNSS probands and have been expanding these families with phenotyping and DNA banking of additional affected and unaffected family members. Subsequent whole exome sequencing (WES) identified 2 candidate genes/mutations (1 in each of 2 families). In both cases, we've generated mouse models of the human mutations. Both of these mice also show short sleep phenotype as seen in human subjects. Another gene (GRM1) was found to harbor distinct mutations in 2 different families. A mouse model of one GRM1 allele also shows short sleep by EEG. These 4 genes (DEC2, ADRB1, NPSR1, and GRM1) still only explain a minority of the ~30 families that underwent initial WES. In this proposal, we plan to continue collecting FNSS subjects from existing `unexplained' families and to continue collecting new probands and their families. Our growing database is an incredible resource for identifying additional FNSS genes/mutations via whole exome sequencing and whole genome sequencing. Studies of this growing list of FNSS genes will help us and others to better understand pathways and brain circuits that contribute to sleep regulation and efficiency. Ultimately, understanding of such biological pathways may lead to novel targets for developing better drugs to improve sleep quality and efficiency.

项目摘要家族性天然短睡眠（FNSS）是一种罕见的门德利人的睡眠形式，受影响的个体终身睡眠的要求大大低于普通人。这些人经常睡4-6个小时夜晚还报告感觉很好。在2009年，我们报道了第一个人类FNSS特征，鉴定因果关系基因/突变。以及模型小鼠中类似短睡眠表型的表征（以及相应的果蝇中的静止活性表型。从那以后，我们已经确定了90多个FNSS概率，并且已经通过表型和额外受影响和未受影响的家庭的表型和DNA库来扩展这些家庭成员。随后的整个外显子组测序（WES）鉴定了2个候选基因/突变（在2个中有1个家庭）。在这两种情况下，我们都生成了人类突变的小鼠模型。这两只老鼠也表明在人类受试者中看到的短睡眠表型。发现另一个基因（GRM1）具有不同的突变在两个不同的家庭中。一个GRM1等位基因的小鼠模型也表现出脑电图的短睡眠。这四个基因（DEC2，ADRB1，NPSR1和GRM1）仍然只解释了约30个经历初始WES的家庭中的少数。在此提案中，我们计划继续从现有的“无法解释的”家庭中收集FNSS主题，并继续收集新的概率及其家人。我们不断增长的数据库是识别的令人难以置信的资源通过整个外显子组测序和整个基因组测序的其他FNSS基因/突变。研究越来越多的FNS基因清单将帮助我们和其他人更好地了解途径和脑电路有助于睡眠调节和效率。最终，对这种生物途径的理解可能导致开发更好的药物以提高睡眠质量和效率的新目标。