Molecular and genetic analysis of sleep ontogeny

睡眠个体发育的分子和遗传分析

基本信息

批准号：
10201379
负责人：
MATTHEW S KAYSER
金额：
$ 40.52万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201379
关键词：
Adolescent Adult Affect Anatomy Behavior Behavioral Behavioral Genetics Binding Brain Cells Cellular Morphology Characteristics Childhood Complex Courtship Data Development Disease Dorsal Drosophila genus Equilibrium Foundations Gene Expression Profiling Genes Genetic Genetic Screening Goals Growth Human Image Impairment Life Link Molecular Molecular Analysis Molecular Genetics Mus Neurocognitive Deficit Neurodevelopmental Disorder Neurons POU Domain Pathology Pathway interactions Pattern Performance Pharmacology Phenotype Pupa RNA Interference Regulation Regulatory Pathway Research Risk Role Seminal Severity of illness Signal Transduction Sleep Sleep Deprivation Sleep disturbances Stress Structure Synapses Testing Therapeutic Time Variant Work base circadian density design fly genetic analysis improved insight juvenile animal knock-down nerve supply neural circuit neurobehavioral neurobehavioral disorder neurodevelopment novel novel therapeutics sleep abnormalities sleep regulation spatiotemporal synaptogenesis transcription factor young adult

项目摘要

Sleep in early life is hypothesized to facilitate structural maturation of the brain. Childhood sleep disturbances portend later neurocognitive deficits and are highly prevalent across neurobehavioral disorders; sleep abnormalities during development may in fact contribute to aberrant neural circuit formation. Improving sleep by targeting regulatory pathways may thus represent a new therapeutic avenue in neurodevelopmental disease. However, the molecular and genetic factors controlling early life sleep remain largely unknown, hindering design of sleep-related strategies. In fact, there are no genes known to specifically influence developmental changes to sleep. Using an RNAi-based genetic screen in Drosophila, we identified a transcription factor, pdm3, that regulates ontogenetic sleep changes. The overall goal of this proposal is to characterize the genetic and molecular pathways controlling sleep ontogenetic changes by investigating the function of PDM3 in Drosophila. Specifically, we will define the cellular mechanisms through which PDM3 controls juvenile sleep (Aim 1) and identify the molecular signals downstream of PDM3 that coordinate sleep ontogeny (Aim 2). We will then manipulate pdm3 to investigate how loss of the juvenile sleep state affects brain and behavioral maturation (Aim 3). Our proposal utilizes a diverse array of approaches, including behavioral, genetic, and imaging. Dissecting the molecular genetic control of sleep ontogeny will yield new insights into the regulation of early life sleep, deepening our understanding of the link between sleep ontogeny and neurobehavioral pathology.

假设在早期睡眠以促进大脑的结构成熟。儿童睡眠障碍预示后来的神经认知缺陷，并且在神经行为疾病中非常普遍；睡觉发育过程中的异常实际上可能导致异常的神经回路形成。改善睡眠因此，通过针对监管途径，可以代表神经发育中的新治疗大道疾病。但是，控制早期睡眠的分子和遗传因素在很大程度上尚不清楚，与睡眠有关的策略的阻碍设计。实际上，没有已知的基因会特别影响睡眠变化。使用果蝇中的基于RNAi的遗传筛选，我们确定了一个转录因子PDM3调节了个体发育睡眠的变化。该提议的总体目标是表征控制睡眠个体发生变化的遗传和分子途径通过研究 PDM3在果蝇中的功能。具体而言，我们将定义PDM3的细胞机制控制青少年睡眠（AIM 1）并识别PDM3下游的分子信号，以协调睡眠个体发育（AIM 2）。然后，我们将操纵PDM3，以研究少年睡眠状态的损失如何影响大脑和行为成熟（目标3）。我们的建议利用了各种各样的方法，包括行为，遗传和成像。剖析睡眠个体发育的分子遗传控制将产生新的深入了解早期生活睡眠的调节，加深我们对睡眠本体发育之间联系的理解和神经行为病理学。