Development of a Synaptic ATP Reporter

突触 ATP 报告基因的开发

基本信息

  • 批准号:
    7977318
  • 负责人:
  • 金额:
    $ 24.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-07-01 至 2012-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Synapses represent key transduction machines that convert incoming electrical information in the form of action potentials into a secreted chemical message which in turn is converted back into a postsynaptic electrical response. The orchestration of these events is thought to underlie critical mechanisms of learning and memory, and dysfunction of synaptic communication is suspected to be central in a number of diseased states of brain function. Synapses however are located at significant distances from cell bodies, and the highly-localized cell biological machinery must rely on local sources of ATP for function. In addition to the ion pumps that are present on both pre and postsynaptic membranes that work to restore ionic balance following activity both compartments contain high concentrations of proteins that must consume ATP in their role carrying out signal transduction, as well as key membrane trafficking events delivering and retrieving proteins and lipids to and from the plasma membrane. Because of these high energy needs, a large fraction of nerve terminals and postsynaptic dendrites are endowed with local mitochondria. Little is known however about intracellular ATP concentrations at these sites, how these concentrations are impacted by synaptic activity, how metabolic needs are coupled to activity, how the presence of local mitochondria impacts local ATP levels, or the extent to which local synaptic ATP generation relies on glycolysis versus oxidative phosphorylation. A local direct reporter of ATP levels is required to access this information. Given that mitochondrial dysfunction has been implicated in a number of neurodegenerative diseases, the ability to directly measure ATP concentration dynamics at individual nerve terminals will be valuable for examining ATP metabolism in these diseased states as well. Here we propose to develop imaging methodology to help fill this information gap. Our approach will be to develop a combined chemo-luminescence and fluorescence approach in the form of a genetically encoded and synaptically targeted ATP indicator that will provide calibrated, dynamic, intracellular synaptic ATP concentration profiles in living nerve terminals. PUBLIC HEALTH RELEVANCE: Information flow in the brain is mediated by transduction of electrical information into chemical information and back again at chemical synapses. The functioning of the human brain relies on the careful orchestration of delivering neurotransmitter-laden vesicles to sites at nerve terminals where they can be used to deliver this chemical message on demand. Many known genetic mutations in diseases such as Parkinson's disease, migraine headache and schizophrenia are linked to proteins that control synapse function. Our work is aimed at understanding the machinery at a molecular level to better ensure the success of future therapies for these types of neuronal diseases. Here we are proposing to develop technologies that will allow us to examine how synapses regulate their energy supply, which is thought to be a critical area of malfunction in certain neurological diseases.
描述(由申请人提供):突触代表将动作电位形式的传入电信息转换为分泌的化学信息的关键转导机器,所述化学信息又被转换回突触后电响应。这些事件的协调被认为是学习和记忆的关键机制的基础,突触通信功能障碍被怀疑是许多脑功能疾病状态的核心。然而,突触位于离细胞体很远的地方,高度定位的细胞生物学机制必须依赖于ATP的局部来源才能发挥作用。除了存在于突触前膜和突触后膜上的离子泵之外,两个隔室都含有高浓度的蛋白质,这些蛋白质在其进行信号转导的作用中必须消耗ATP,以及关键的膜运输事件,将蛋白质和脂质递送到质膜和从质膜取回蛋白质和脂质。由于这些高能量需求,大部分神经末梢和突触后树突被赋予局部线粒体。然而,人们对这些位点的细胞内ATP浓度知之甚少,这些浓度如何受到突触活动的影响,代谢需求如何与活动耦合,局部线粒体的存在如何影响局部ATP水平,或局部突触ATP生成依赖于糖酵解与氧化磷酸化的程度。需要ATP水平的当地直接报告人访问此信息。鉴于线粒体功能障碍与许多神经退行性疾病有关,直接测量单个神经末梢处ATP浓度动态的能力对于检查这些疾病状态下的ATP代谢也将是有价值的。在这里,我们建议开发成像方法,以帮助填补这一信息空白。我们的方法将是开发一种组合的化学发光和荧光方法,其形式为遗传编码和突触靶向的ATP指示剂,其将在活神经末梢中提供校准的、动态的、细胞内突触ATP浓度分布。 公共卫生相关性:大脑中的信息流是通过将电信息转换为化学信息并在化学突触处再次转换回来来介导的。人类大脑的功能依赖于将载有神经递质的囊泡递送到神经末梢的位点的精心编排,在那里它们可以用于按需递送这种化学信息。许多已知的疾病基因突变,如帕金森病,偏头痛和精神分裂症,都与控制突触功能的蛋白质有关。我们的工作旨在了解分子水平上的机制,以更好地确保未来治疗这些类型的神经元疾病的成功。在这里,我们建议开发技术,使我们能够检查突触如何调节其能量供应,这被认为是某些神经系统疾病中功能障碍的关键区域。

项目成果

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Timothy Aidan Ryan其他文献

Timothy Aidan Ryan的其他文献

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{{ truncateString('Timothy Aidan Ryan', 18)}}的其他基金

Metabolic Vulnerability of Synapses in Neurodegenerative Disease
神经退行性疾病中突触的代谢脆弱性
  • 批准号:
    10578785
  • 财政年份:
    2020
  • 资助金额:
    $ 24.94万
  • 项目类别:
Metabolic Vulnerability of Synapses in Neurodegenerative Disease
神经退行性疾病中突触的代谢脆弱性
  • 批准号:
    10365919
  • 财政年份:
    2020
  • 资助金额:
    $ 24.94万
  • 项目类别:
Identification of synaptic alpha2delta binding partners
突触 alpha2delta 结合伙伴的鉴定
  • 批准号:
    8660359
  • 财政年份:
    2013
  • 资助金额:
    $ 24.94万
  • 项目类别:
Identification of synaptic alpha2delta binding partners
突触 alpha2delta 结合伙伴的鉴定
  • 批准号:
    8597614
  • 财政年份:
    2013
  • 资助金额:
    $ 24.94万
  • 项目类别:
Development of a Synaptic ATP Reporter
突触 ATP 报告基因的开发
  • 批准号:
    8066969
  • 财政年份:
    2010
  • 资助金额:
    $ 24.94万
  • 项目类别:
Quantitative Mapping of Molecules and Release Properties at Nerve Terminals
神经末梢分子和释放特性的定量图谱
  • 批准号:
    7781100
  • 财政年份:
    2009
  • 资助金额:
    $ 24.94万
  • 项目类别:
Quantitative mapping of molecules and release properties at nerve terminals
神经末梢分子和释放特性的定量图谱
  • 批准号:
    8825287
  • 财政年份:
    2009
  • 资助金额:
    $ 24.94万
  • 项目类别:
Quantitative Mapping of Molecules and Release Properties at Nerve Terminals
神经末梢分子和释放特性的定量图谱
  • 批准号:
    8586902
  • 财政年份:
    2009
  • 资助金额:
    $ 24.94万
  • 项目类别:
Quantitative Mapping of Molecules and Release Properties at Nerve Terminals
神经末梢分子和释放特性的定量图谱
  • 批准号:
    8389677
  • 财政年份:
    2009
  • 资助金额:
    $ 24.94万
  • 项目类别:
Quantitative Mapping of Molecules and Release Properties at Nerve Terminals
神经末梢分子和释放特性的定量图谱
  • 批准号:
    8196919
  • 财政年份:
    2009
  • 资助金额:
    $ 24.94万
  • 项目类别:

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