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Role of Prokineticin 2 in Regulating Sleep in Zebrafish

Prokineticin 2 在调节斑马鱼睡眠中的作用

基本信息

批准号：
10056992
负责人：
David Aaron Prober
金额：
$ 36.09万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056992
关键词：
Address Affect American Anatomy Animals Anterior Hypothalamus Arousal Behavior Behavioral Binding Brain Chronic Circadian Rhythms Data Defect Detection Development Disease Drug Targeting Economic Burden Exhibits Exposure to G-Protein-Coupled Receptors Galanin Genes Genetic Genetic study Homologous Gene Human Hypothalamic structure Infusion procedures Larva Lead Light Mammals Masks Mediating Mental Depression Modeling Modernization Motor Activity Mutant Strains Mice Neonatal Neurologic Neurons Neuropeptides Orthologous Gene PROKR1 gene Peptides Pharmacology Phenotype Play Regulatory Pathway Retina Rodent Role Schizophrenia Signal Transduction Sleep Sleep Disorders Sleep Disorders Therapy Sleep disturbances Societies Testing Therapeutic Time Transforming Growth Factors Wakefulness Work Zebrafish autism spectrum disorder awake circadian circadian pacemaker cost cytokine effective therapy experimental study factor A field study in vivo light effects locus ceruleus structure loss of function melanopsin mutant neural circuit neuropsychiatric disorder noradrenergic novel therapeutics optogenetics overexpression preoptic nucleus sleep abnormalities small molecule tool

项目摘要

Light affects sleep indirectly by entraining the circadian clock, but also directly and rapidly via a phenomenon known as the masking or direct effect of light on behavior. Masking refers to the observation that light exposure at night induces sleep in nocturnal animals and suppresses sleep in diurnal animals, including humans, whereas dark exposure during the day inhibits sleep in nocturnal animals. While masking is widespread in the animal kingdom, the mechanisms that mediate masking are largely unknown. Understanding mechanisms that regulate sleep is important because over 10% of Americans suffer from chronic sleep disorders that have poor therapeutic options and cause an annual economic burden of $100 billion. Understanding how masking in particular affects sleep is important because at least some of the sleep disruption observed in modern societies results from masking due to widespread exposure to artificial light at night. Our preliminary experiments using zebrafish suggest that the neuropeptide prokineticin 2 (Prok2) regulates masking. To our knowledge, this is the first gene shown to regulate masking beyond the initial step of light detection by melanopsin in the retina, and thus it provides a foothold to explore the genetic and neurological mechanisms through which light directly affects sleep. Although a similar phenotype was observed in rodents, a role in masking was not explored, and the developmental defects of prok2 mutant mice confound sleep studies. The zebrafish is a vertebrate model that exhibits behavioral, anatomical, genetic and pharmacological conservation of mammalian sleep. While the zebrafish has some limitations as a sleep model, its amenability to genetic, optogenetic and pharmacological approaches, as well as its transparency and relatively simple yet conserved vertebrate brain, and the lack of developmental defects in prok2 mutant animals, provide advantages for sleep studies that we exploit in this proposal. The zebrafish is particularly appropriate for studying mechanisms that may underlie masking in humans because it is a diurnal vertebrate. In Specific Aim 1 we use gain- and loss-of-function genetics, as well as optogenetic and chemogenetic tools, to test the hypotheses that Prok2 and prok2-expressing neurons regulate masking. We also test whether our findings for Prok2 apply to other peptides that have been proposed to regulate behavior in a manner similar to Prok2. In Specific Aim 2, we explore potential mechanisms through which Prok2 regulates masking, such as by regulating the activity of the noradrenergic locus coeruleus (Aim 2A), the expression of the sleep-promoting neuropeptide galanin in the hypothalamus (Aim 2B) or other sleep regulatory pathways. These studies will for the first time identify genes and neurons in the brain that regulate masking, and thus provide a basis to study the genetic and neurological mechanisms that underlie this phenomenon. Because Prok2 acts via G-protein coupled receptors, which are amenable to small molecule modulation, this work may eventually lead to novel therapies for sleep disorders and for neuropsychiatric disorders that are exacerbated by disrupted sleep.

光线通过调节生物钟间接影响睡眠，但也通过一种现象直接而迅速地影响睡眠

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Discovery of Hypocretin/Orexin Ushers in a New Era of Sleep Research.

DOI：
10.1016/j.tins.2017.11.007
发表时间：
2018-03
期刊：
Trends in neurosciences
影响因子：
15.9
作者：
Prober DA
通讯作者：
Prober DA

Genetic Analysis of Histamine Signaling in Larval Zebrafish Sleep.

DOI：
10.1523/eneuro.0286-16.2017
发表时间：
2017-01
期刊：
eNeuro
影响因子：
3.4
作者：
Chen A;Singh C;Oikonomou G;Prober DA
通讯作者：
Prober DA

Publisher Correction: Prokineticin receptor 2 affects GnRH3 neuron ontogeny but not fertility in zebrafish.

出版商更正：前动力蛋白受体 2 影响 GnRH3 神经元个体发育，但不影响斑马鱼的生育力。

DOI：
10.1038/s41598-020-65551-7
发表时间：
2020
期刊：
Scientific reports
影响因子：
4.6
作者：
Bassi,Ivan;Luzzani,Francesca;Marelli,Federica;Vezzoli,Valeria;Cotellessa,Ludovica;Prober,DavidA;Persani,Luca;Gothilf,Yoav;Bonomi,Marco
通讯作者：
Bonomi,Marco

Genetic and neuronal regulation of sleep by neuropeptide VF.

DOI：
10.7554/elife.25727
发表时间：
2017-11-06
期刊：
eLife
影响因子：
7.7
作者：
Lee DA;Andreev A;Truong TV;Chen A;Hill AJ;Oikonomou G;Pham U;Hong YK;Tran S;Glass L;Sapin V;Engle J;Fraser SE;Prober DA
通讯作者：
Prober DA

Linking immunity and sickness-induced sleep.

将免疫力与疾病引起的睡眠联系起来。