Gene Transfer for Cataplexy of Narcolepsy
Gene Transfer for Cataplexy of Narcolepsy
批准号:
9238032
负责人:
Meng Liu
金额:
$36.9万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-15 至 2021-06-30
关键词:
AffectAmygdaloid structureAngerAutomobile DrivingBehaviorBrainCataplexyCell NucleusCoyotesDataDevelopmentDiseaseEmotionalEmotionsFrightFundingGene TransferGenesGoalsHumorIn VitroInternal Ribosome Entry SiteKnockout MiceLaughterLinkMapsMeasuresMiningMusMuscleMuscle TonusNarcolepsyNerve DegenerationNeuronsNeuropeptidesNeurosciencesOpsinPaperPhenotypePontine structurePopulationPublicationsPublishingRecombinant adeno-associated virus (rAAV)ResearchResearch PersonnelSiteSleepSleep DisordersSymptomsTestingTracerUrineabstractinggamma-Aminobutyric Acidhypocretinin vivoinhibitory neuronnerve supplyneural circuitneuron lossnoveloptogeneticspreventrepairedtool
中文摘要
摘要
我是一名年轻的新研究者,拥有可靠的发表记录,正在使用新工具来纠正
睡眠障碍、发作性睡病中的特定回路。这种疾病与特定的神经元损失有关
含有神经肽食欲素,也称为下丘脑分泌素。我的研究是第一个证明这一点的研究
将食欲素基因转移到发作性睡病小鼠的大脑中可以阻止猝倒。事实上,食欲素基因转移到
中枢神经系统中的一些神经元群已被证明是无效的,这表明只有特定的替代物
神经元可以修复发作性睡病行为。该项目将继续关注猝倒症,这是一个重要的
发作性睡病的显着症状。猝倒是指清醒时肌张力突然丧失,
通常由强烈的情绪触发,包括积极的(例如笑声、幽默)和消极的(例如愤怒、
恐惧或突然的惊讶)情绪。目前尚不清楚情绪如何引发猝倒。我试图确定这一点
通过结合食欲素基因转移、光遗传学和新颖的脑回路绘图工具来限制回路
表型和投射特异性神经元的特定基因的表达。驱动的总体假设
目的是在强烈情绪期间,GABA 从杏仁核中央核 (CeA) 输入到
背外侧脑桥 (vlPAG/LC/LPT) 通过抑制负责脑桥的脑桥回路来引发猝倒
保持肌肉张力。初步数据支持这一假设,因为光遗传学抑制或
将食欲素插入投射到 vLPAG/LC/LPT 的 CeA 杏仁核神经元中会降低情绪
诱发猝倒。提出了五个目标来检验总体假设。拟议的目标是相互的
支持、假设驱动、具有明确的目标和明确的终点。广泛的初步数据显示
支持该方法的假设和可行性。资助期结束时,该项目将
已经确定了一个有意义的神经回路。这将对潜力的开发产生重大影响
可以选择性地针对该回路的疗法,包括药物制剂。
英文摘要
Abstract
I am a new young investigator with a proven publication record who is using new tools to correct
specific circuits in the sleep disorder, narcolepsy. This disorder is linked to a specific loss of neurons
containing the neuropeptide orexin, also known as hypocretin. Mine was the first study to demonstrate that
orexin gene transfer into the brains of narcoleptic mice blocks cataplexy. Indeed, orexin gene transfer into
some neuron populations in the CNS has proven to be ineffective indicating that only specific surrogate
neurons can repair narcoleptic behavior. This project will continue to focus on cataplexy, an important
distinguishing symptom of narcolepsy. Cataplexy is a sudden loss of muscle tone during waking and it is
often triggered by strong emotions, including both positive (e.g. laughter, humor) and negative (e.g. anger,
fear or sudden surprise) emotions. It is not known how emotions trigger cataplexy. I seek to identify this
circuit by combining orexin gene transfer, optogenetics and novel brain circuit mapping tools that restrict
expression of specific genes to phenotype and projection-specific neurons. The overall hypothesis driving the
aims is that during strong emotions GABA input from the central nucleus of the amygdala (CeA) to the
dorsolateral pons (vlPAG/LC/LPT) triggers cataplexy by inhibiting the pontine circuit responsible for
maintaining muscle tone. Preliminary data supports this hypothesis because optogenetic inhibition or
insertion of orexin into the CeA amygdala neurons projecting to the vlPAG/LC/LPT decreases emotion-
induced cataplexy. Five aims are proposed to test the overall hypothesis. The proposed aims are mutually
supporting, hypothesis driven, with clear objectives and definite endpoints. Extensive preliminary data show
support for the hypothesis and feasibility of the approach. At the end of the funding period the project will
have identified a meaningful neural circuit. This will have a significant impact in the development of potential
therapies, including pharmacological agents, that can be selectively directed to this circuit.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Sleep, Pericytes, and Alzheimer's Disease
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批准号:10448572
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项目类别:
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资助金额:$195.5万
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财政年份:2022
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负责人:Meng Liu
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依托单位:
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批准号:9975333
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项目类别:
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资助金额:$22.43万
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财政年份:2020
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负责人:Meng Liu
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依托单位:
Cellular Mechanism underlying emotional problems of Alzheimer's disease
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批准号:10159839
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项目类别:
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资助金额:$18.69万
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财政年份:2020
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负责人:Meng Liu
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依托单位:
Circuit Mapping for emotion-induced cataplexy of Narcolepsy
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批准号:9299015
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项目类别:
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资助金额:$18.14万
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财政年份:2017
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负责人:Meng Liu
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依托单位:
Hypocretin and its receptors Gene Transfer for Narcolepsy
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批准号:8548216
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项目类别:
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资助金额:$12.62万
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财政年份:2012
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负责人:Meng Liu
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依托单位:
Hypocretin and its receptors Gene Transfer for Narcolepsy
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批准号:8717554
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项目类别:
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资助金额:$12.62万
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财政年份:2012
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负责人:Meng Liu
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依托单位:
Hypocretin and its receptors Gene Transfer for Narcolepsy
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批准号:8383048
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项目类别:
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资助金额:$12.62万
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财政年份:2012
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负责人:Meng Liu
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依托单位: