Deciphering the molecular interplay of sleep and neurodegeneration with Drosophila
破译果蝇睡眠和神经退行性变的分子相互作用
基本信息
- 批准号:10554337
- 负责人:
- 金额:$ 62.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAnimalsBehavior TherapyBehavioralBehavioral ModelBrainBrain DiseasesCoupledDataDefectDegenerative DisorderDementiaDeteriorationDimensionsDiseaseDisease ProgressionDrosophila genusEnhancersFoundationsFrontotemporal DementiaFunctional disorderGenesGeneticGenetic ScreeningGenomicsGoalsHumanImpaired cognitionInterventionInvestigationLinkLongevityMechanicsModalityModelingModificationMolecularMotor Neuron DiseaseMusNerve DegenerationNeurodegenerative DisordersNeurogliaNeuronsPathologyPathway interactionsPhenotypeProcessPropertyProteinsRNA InterferenceResearchRisk FactorsSCA2 proteinSeriesSleepSleep DeprivationSleep DisordersSleep disturbancesSleeplessnessSystemTDP-43 aggregationTestingTherapeuticTimeToxic effectWorkabeta accumulationcombatepitranscriptomicsflygene interactiongenetic approachhuman diseaseimprovement on sleepinsightknock-downmodifiable risknew therapeutic targetnovelnovel therapeuticsprotein TDP-43resiliencesleep abnormalitiessleep regulation
项目摘要
PROJECT SUMMARY
Accumulating evidence strongly supports the idea that sleep is a crucial variable in neurodegenerative disease:
disease progression disrupts sleep, and disrupted sleep worsens brain degeneration. Sleep is thought to
represent a powerful untapped therapeutic modality through which neurodegeneration can be modified. Yet how
sleep and neurodegeneration are coupled at a mechanistic level is poorly understood. Defining cellular and
molecular links between sleep and neurodegeneration has been difficult, limiting the ability to pursue sleep
modification as a therapeutic avenue. We propose leveraging a neurodegeneration model in Drosophila to
dissect mechanisms of disrupted sleep in detail, including use of high throughput genetic screens available in
simple systems, with the goal of defining molecular pathways linking sleep and brain integrity.
We have found that expression of the human neurodegenerative disease protein TDP43 (linked to
Alzheimer’s, frontotemporal dementia, and motor neuron disease) causes a robust sleep impairment. Our initial
data suggest that the Drosophila sleep phenotype results from dysfunction in glia, which are known to be critically
involved in sleep regulation. Importantly, expression of TDP43 in glia also causes brain degeneration and
shortened lifespan in flies, providing a strong rationale for investigation of TDP43 as a key link between sleep
and neurodegeneration. Because TDP43 pathology has been described in many human neurodegenerative
diseases including Alzheimer’s, focused study of the mechanisms linking TDP43 with sleep are likely to be
broadly relevant.
Here we will investigate the molecular mechanisms linking TDP43-associated brain degeneration and
sleep. In Aim 1, we propose to define the glial subtype critical for the sleep effect and examine how sleep loss
affects the subcellular localization and accumulation of TDP43. A preliminary genetic screen for modifiers of
TDP43-induced sleep dysfunction has already defined several suppressors, including Ataxin-2, a known human
disease gene that interacts with TDP43 in neurons. In Aim 2, we will examine this suppressor and others in detail
to define molecular and cellular mechanisms of the interaction. Finally, our preliminary data indicate that
restriction of sleep opportunity (Sleep Restriction Therapy, SRT) can reverse sleep defects in TDP43 flies. In
Aim 3 we will examine SRT in TDP43 flies, and conduct a genetic screen to define the molecular pathways
through which SRT improves sleep in this brain degeneration model. Taken together these aims will shed new
light on the molecular and genetic links between sleep dysfunction and brain degeneration, and provide the
foundation for novel therapeutic targets that leverage sleep to promote brain integrity.
项目摘要
越来越多的证据强烈支持睡眠是神经退行性疾病的一个关键变量的观点:
疾病的进展会扰乱睡眠,而睡眠的中断会导致大脑退化。睡眠被认为
代表了一种强大的未开发的治疗方式,通过它可以改变神经变性。但是他又怎
睡眠和神经退行性变在机制水平上是耦合的,这一点还知之甚少。定义蜂窝和
睡眠和神经退化之间的分子联系一直很困难,限制了追求睡眠的能力
作为一种治疗手段。我们建议利用果蝇的神经变性模型,
详细剖析睡眠中断的机制,包括使用高通量基因筛选,
简单的系统,目标是定义连接睡眠和大脑完整性的分子通路。
我们已经发现,人神经退行性疾病蛋白TDP 43的表达(与人神经退行性疾病蛋白TDP 43的表达相关)与神经退行性疾病蛋白TDP 43的表达相关。
阿尔茨海默氏症、额颞叶痴呆症和运动神经元疾病)会导致严重的睡眠障碍。我们最初
数据表明,果蝇睡眠表型是由神经胶质功能障碍引起的,
参与睡眠调节。重要的是,TDP 43在神经胶质中的表达也引起脑变性,
缩短苍蝇的寿命,为研究TDP 43作为睡眠和睡眠之间的关键联系提供了强有力的理由。
和神经退化由于TDP 43病理学已经在许多人类神经退行性疾病中被描述,
包括阿尔茨海默氏症在内的疾病,将TDP 43与睡眠联系起来的机制的重点研究很可能是
广泛相关。
在这里,我们将研究与TDP 43相关的脑变性和脑损伤之间的分子机制。
睡吧在目标1中,我们建议定义对睡眠效应至关重要的神经胶质亚型,并研究睡眠丧失如何影响神经胶质细胞的功能。
影响TDP 43的亚细胞定位和积累。初步遗传筛选的修饰剂,
TDP 43诱导的睡眠功能障碍已经确定了几种抑制因子,包括Ataxin-2,一种已知的人类
与神经元中的TDP 43相互作用的疾病基因。在目标2中,我们将详细研究这种抑制器和其他抑制器
以确定相互作用的分子和细胞机制。最后,我们的初步数据表明,
限制睡眠机会(睡眠限制疗法,SRT)可以逆转TDP 43果蝇的睡眠缺陷。在
目的3我们将在TDP 43果蝇中检测SRT,并进行遗传筛选以确定分子途径
通过SRT改善大脑退化模型的睡眠。这些目标合在一起,
阐明睡眠功能障碍和大脑退化之间的分子和遗传联系,并提供
新的治疗目标,利用睡眠促进大脑完整性的基础。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Nancy M Bonini其他文献
Nancy M Bonini的其他文献
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{{ truncateString('Nancy M Bonini', 18)}}的其他基金
Deciphering the molecular interplay of sleep and neurodegeneration with Drosophila
破译果蝇睡眠和神经退行性变的分子相互作用
- 批准号:
10370176 - 财政年份:2022
- 资助金额:
$ 62.88万 - 项目类别:
Deciphering the molecular interplay of sleep and neurodegeneration with Drosophila
破译果蝇睡眠和神经退行性变的分子相互作用
- 批准号:
10358884 - 财政年份:2021
- 资助金额:
$ 62.88万 - 项目类别:
Molecular Genetic Insight into Neurodegenerative Disease from Drosophila
果蝇神经退行性疾病的分子遗传学见解
- 批准号:
10532838 - 财政年份:2016
- 资助金额:
$ 62.88万 - 项目类别:
Molecular Genetic Insight into Neurodegenerative Disease from Drosophila
果蝇神经退行性疾病的分子遗传学见解
- 批准号:
9156199 - 财政年份:2016
- 资助金额:
$ 62.88万 - 项目类别:
Molecular Genetic Insight into Neurodegenerative Disease from Drosophila
果蝇神经退行性疾病的分子遗传学见解
- 批准号:
10534678 - 财政年份:2016
- 资助金额:
$ 62.88万 - 项目类别:
Molecular Genetic Insight into Neurodegenerative Disease from Drosophila
果蝇神经退行性疾病的分子遗传学见解
- 批准号:
10063573 - 财政年份:2016
- 资助金额:
$ 62.88万 - 项目类别:
Interplay of the microbiome and the brain in neurodegenerative disease
微生物组和大脑在神经退行性疾病中的相互作用
- 批准号:
8755389 - 财政年份:2014
- 资助金额:
$ 62.88万 - 项目类别:
Ataxin-2 as a genetic risk factor for ALS: New insights into neurodegeneration
Ataxin-2 作为 ALS 的遗传危险因素:对神经退行性变的新见解
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8675969 - 财政年份:2011
- 资助金额:
$ 62.88万 - 项目类别:
Ataxin-2 as a genetic risk factor for ALS: New insights into neurodegeneration
Ataxin-2 作为 ALS 的遗传危险因素:对神经退行性变的新见解
- 批准号:
8471799 - 财政年份:2011
- 资助金额:
$ 62.88万 - 项目类别:
Ataxin-2 as a genetic risk factor for ALS: New insights into neurodegeneration
Ataxin-2 作为 ALS 的遗传危险因素:对神经退行性变的新见解
- 批准号:
8322589 - 财政年份:2011
- 资助金额:
$ 62.88万 - 项目类别:
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