Adaptations to chronic activation of BK channels by ethanol: Contribution to dependence and tolerance

乙醇对 BK 通道慢性激活的适应:对依赖性和耐受性的贡献

基本信息

  • 批准号:
    10703253
  • 负责人:
  • 金额:
    $ 55.3万
  • 依托单位:
  • 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:
    2020-01-15 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

SUMMARY Large conductance, voltage- and calcium-activated (BK) channels are a molecular target of ethanol. Our data indicate that ethanol-induced activation of BK channels facilitates the escalation of voluntary ethanol consumption in mice made dependent to ethanol. We therefore hypothesize that molecular adaptations resulting from chronic activation of BK channels by ethanol facilitate the progression to dependence, possibly by lowering ethanol sensitivity. Accordingly, our project aims to elucidate the molecular identity of BK-dependent adaptations (Aim 1, R21 phase) and to test their functional implication in the transition to dependence (Aim 2, R33 phase) and in the control of ethanol sensitivity (Aim 3, R33 phase). We will take advantage of a knockin mouse expressing BK channels that are insensitive to ethanol but function normally otherwise to identify molecular adaptations to chronic ethanol that selectively result from the action of ethanol on BK channels. Molecular adaptations that emerge in brain regions relevant to the motivational and affective effects of ethanol (ventral tegmental area, amygdala, prelimbic prefrontal cortex, and habenula) will be examined in a well-validated mouse model of ethanol dependence. We will leverage the unprecedented sensitivity and accuracy of data-independent acquisition mass spectrometry to quantify changes in protein abundance across the entire proteome. Furthermore, we will implement weighted correlation network analysis to identify proteins that are the most likely to drive concerted changes in abundance across modules of co-expressed proteins. Nine of these proteins will be selected at the end of the R21 phase for functional analysis during the R33 phase. We will use virally mediated RNA interference to knock down candidate proteins in targeted brain regions and evaluate the influence of these proteins on the time-course, amplitude and persistence of drinking escalation in ethanol-dependent mice. We predict that some of the proteins controlling drinking escalation will also control acute sensitivity to ethanol, such that their up- or down-regulation in ethanol-dependent mice would progressively decrease sensitivity to ethanol. Accordingly, we will also examine the impact of local protein knockdown on the reinforcing and anxiolytic effects of ethanol. Altogether, the proposed experiments are designed to identify novel molecular determinants of vulnerability to alcohol use disorders. Our proposal is relevant to the focus of FOA PAR-18-659 because the proteins identified in this project may pinpoint molecular mechanisms underlying differential sensitivity to alcohol in the human population.
总结 大电导、电压和钙激活(BK)通道是乙醇的分子靶点。我们的数据 表明乙醇诱导的BK通道激活促进自发乙醇的增加 消耗依赖于乙醇的小鼠。因此,我们假设,分子适应导致 从慢性激活BK通道的乙醇促进发展的依赖性,可能是通过降低 乙醇敏感性因此,我们的项目旨在阐明BK依赖性适应的分子身份 (Aim 1,R21阶段),并测试其在向依赖性过渡中的功能含义(目标2,R33阶段) 控制乙醇敏感性(Aim 3,R33阶段)。我们将利用一个敲入老鼠 表达BK通道,其对乙醇不敏感,但功能正常,以识别分子 对慢性乙醇的适应,选择性地由乙醇对BK通道的作用引起。分子 适应出现在大脑区域相关的动机和情感的影响,乙醇(腹 被盖区、杏仁核、前边缘前额叶皮层和缰核)进行检查 乙醇依赖模型。我们将利用前所未有的敏感性和准确性, 采集质谱以量化整个蛋白质组中蛋白质丰度的变化。 此外,我们将实施加权相关网络分析,以确定最有可能的蛋白质 来驱动共表达蛋白质模块之间丰度的协同变化。这些蛋白质中有9种 在R21阶段结束时选择用于R33阶段的功能分析。我们将使用病毒介导的 RNA干扰敲除目标大脑区域中的候选蛋白质并评估其影响 蛋白质对酒精依赖小鼠饮酒增加的时间进程、幅度和持续性的影响。我们 预测一些控制饮酒升级的蛋白质也将控制对乙醇的急性敏感性, 在乙醇依赖小鼠中上调或下调它们会逐渐降低对乙醇的敏感性。 因此,我们也将研究局部蛋白质敲低对增强和抗焦虑作用的影响。 乙醇。总而言之,所提出的实验被设计为鉴定新的分子决定簇, 易患酒精使用障碍。我们的建议与FOA PAR-18-659的重点相关,因为 在这个项目中发现的蛋白质可以精确地确定对酒精敏感性差异的分子机制 在人类中。

项目成果

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Candice Contet其他文献

Candice Contet的其他文献

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{{ truncateString('Candice Contet', 18)}}的其他基金

Role of glucocorticoid receptor-mediated mRNA decay in alcohol dependence
糖皮质激素受体介导的 mRNA 衰减在酒精依赖中的作用
  • 批准号:
    10811212
  • 财政年份:
    2023
  • 资助金额:
    $ 55.3万
  • 项目类别:
Adaptations to chronic activation of BK channels by ethanol: Contribution to dependence and tolerance
乙醇对 BK 通道慢性激活的适应:对依赖性和耐受性的贡献
  • 批准号:
    9895344
  • 财政年份:
    2020
  • 资助金额:
    $ 55.3万
  • 项目类别:
Adaptations to chronic activation of BK channels by ethanol: Contribution to dependence and tolerance
乙醇对 BK 通道慢性激活的适应:对依赖性和耐受性的贡献
  • 批准号:
    10685085
  • 财政年份:
    2020
  • 资助金额:
    $ 55.3万
  • 项目类别:
Novel circuit mechanism of alcohol dependence vulnerability following early-life adversity
早年逆境后酒精依赖脆弱性的新回路机制
  • 批准号:
    10058181
  • 财政年份:
    2020
  • 资助金额:
    $ 55.3万
  • 项目类别:
Activation of the parasubthalamic nucleus in alcohol dependence
酒精依赖中副丘脑核的激活
  • 批准号:
    10377563
  • 财政年份:
    2018
  • 资助金额:
    $ 55.3万
  • 项目类别:
Activation of the parasubthalamic nucleus in alcohol dependence
酒精依赖中副丘脑核的激活
  • 批准号:
    9899906
  • 财政年份:
    2018
  • 资助金额:
    $ 55.3万
  • 项目类别:
Role of BK Channel Interactome in Excessive Ethanol Drinking
BK 通道相互作用组在过量乙醇饮酒中的作用
  • 批准号:
    8231180
  • 财政年份:
    2011
  • 资助金额:
    $ 55.3万
  • 项目类别:
Role of BK Channel Interactome in Excessive Ethanol Drinking
BK 通道相互作用组在过量乙醇饮酒中的作用
  • 批准号:
    8516915
  • 财政年份:
    2011
  • 资助金额:
    $ 55.3万
  • 项目类别:
Role of BK Channel Interactome in Excessive Ethanol Drinking
BK 通道相互作用组在过量乙醇饮酒中的作用
  • 批准号:
    8707289
  • 财政年份:
    2011
  • 资助金额:
    $ 55.3万
  • 项目类别:
Role of BK Channel Interactome in Excessive Ethanol Drinking
BK 通道相互作用组在过量乙醇饮酒中的作用
  • 批准号:
    8327766
  • 财政年份:
    2011
  • 资助金额:
    $ 55.3万
  • 项目类别:

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