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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：
10676762
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/10676762
关键词：
ADRB1 gene Acceleration Affect Alleles American Biological Biology Brain Candidate Disease Gene Cessation of life Chronic Code Collection DNA Databases DNA Library Databases Detection Drosophila genus Electroencephalography Epidemiology Family Family member GRM1 gene Genes Genetic Genome Grant Health Homeostasis Hour Human Human Biology Immunity Impairment In Vitro Individual Induced Mutation Introns Investments 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 autosome circadian clinical database exome exome sequencing genome sequencing human subject improvement on sleep in vivo interest mortality mouse model novel proband psychosocial sleep behavior sleep pattern sleep quality sleep quantity sleep regulation trait whole genome

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.

项目概要家族性自然短睡眠 (FNSS) 是一种罕见的孟德尔睡眠形式，受影响的个体将终生处于睡眠状态。睡眠需求明显低于普通人。这些人通常每天睡4-6小时晚上尚未报告感觉休息良好。 2009 年，我们报告了第一个人类 FNSS 特征，即确定致病因素基因/突变。以及模型小鼠中类似的短睡眠表型的表征（以及相应的果蝇的休息活动表型）。此后，我们已鉴定出 90 多名 FNSS 先证者，并已通过对其他受影响和未受影响的家庭进行表型分析和 DNA 库来扩大这些家庭成员。随后的全外显子组测序 (WES) 确定了 2 个候选基因/突变（2 个基因/突变中各有 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。这两只老鼠还表现出在人类受试者中观察到的短睡眠表型。另一个基因 (GRM1) 被发现含有不同的突变在2个不同的家庭。一种 GRM1 等位基因的小鼠模型也通过脑电图显示睡眠时间较短。这4个基因（DEC2、ADRB1、NPSR1 和 GRM1）仍然只能解释接受初始 WES 的约 30 个家庭中的少数。在这项提案中，我们计划继续从现有的“无法解释”的家庭中收集 FNSS 受试者，并继续收集新的先证者及其家人。我们不断增长的数据库是一个令人难以置信的识别资源通过全外显子组测序和全基因组测序获得额外的 FNSS 基因/突变。对此的研究不断增加的 FNSS 基因列表将帮助我们和其他人更好地了解影响这些基因的通路和大脑回路。有助于睡眠调节和效率。最终，对此类生物途径的理解可能会导致开发更好的药物以改善睡眠质量和效率的新目标。