Mechanism of Resistance Artery Contraction

动脉收缩阻力机制

基本信息

项目摘要

Pressure-induced (myogenic) tone is a physiological response centrally involved in autoregulation of blood flow in the brain. A fundamental mechanism involved in the regulation of cerebral artery constriction is depolarization of the smooth muscle cell membrane and increased Ca2+ entry. We have recently identified a cerebrovascular cation channel that could play a major role in both the depolarization and Ca2+-entry processes. Additional preliminary data indicate that this cation channel may be a member of the mammalian transient receptor potential (Trp) family. In the proposed studies, we will characterized the properties of these channels and determine their functional roles in the cerebral circulation. Specific Aim 1. To elucidate the biophysical and pharmacological properties of cation channels activated by cell swelling or increased pressure in cerebrovascular smooth muscle cells and the signal transduction pathways involved in their regulation. These experiments will provide evidence that will establish the role of these channels in pressure-induced depolarization of cerebral artery myocytes. Specific Aim 2. To establish the presence and functional roles of Trp channels in cerebral artery smooth muscle cells. This aim will determine which of the Trp channels are present in cerebrovascular muscle cells and what physiological roles they serve in cerebral resistance arteries. These studies will be performed using a unique combination of approaches from molecular to whole tissue levels to provide an integrated picture of cerebral artery contractile mechanisms involving membrane potential and regulation of [Ca2+]i. State-of-the-art techniques will be employed including membranes potential, cell Ca2+, and diameter measurements in intact arteries, ion channel and cell Ca2+, measurements in freshly isolated vascular smooth muscle cells, and anti- sense oligodeoxynucleotide strategies to suppress Trp channel function. The proposed studies should significantly advance our understanding of the role of cationic channels in the regulation of vascular tone in the brain and indicate novel targets for agents that could be used to correct pathological alterations in cerebral blood flow.
压力诱导(肌源性)张力是一种生理反应,主要参与大脑中血液流动的自动调节。参与调节大脑动脉收缩的一个基本机制是平滑肌细胞膜去极化和钙离子内流增加。我们最近发现了一种脑血管阳离子通道,它可能在去极化和钙离子进入过程中发挥重要作用。更多的初步数据表明,这个阳离子通道可能是哺乳动物瞬时受体潜力(Trp)家族的成员。在拟议的研究中,我们将表征这些通道的特性,并确定它们在脑循环中的功能作用。具体目的1.阐明细胞肿胀或压力升高激活的脑血管平滑肌细胞阳离子通道的生物物理和药理学特性及其调控的信号转导途径。这些实验将为确定这些通道在压力诱导的大脑动脉肌细胞去极化中的作用提供证据。具体目的2.建立TRP通道在大脑动脉平滑肌细胞中的存在及其功能作用。这一目标将确定脑血管肌肉细胞中存在哪些Trp通道,以及它们在脑阻力动脉中发挥什么生理作用。这些研究将使用从分子到整个组织水平的独特组合,以提供涉及膜电位和[Ca~(2+)]i调节的脑动脉收缩机制的完整图景。将采用最先进的技术,包括完整动脉的膜电位、细胞Ca~(2+)和直径测量、离子通道和细胞Ca~(2+)测量、新鲜分离的血管平滑肌细胞的测量,以及抑制Trp通道功能的反义寡核苷酸策略。这项拟议的研究将极大地促进我们对阳离子通道在调节大脑血管张力中的作用的理解,并为可用于纠正脑血流病理变化的药物指明新的靶点。

项目成果

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JOSEPH ELLIOTT BRAYDEN其他文献

JOSEPH ELLIOTT BRAYDEN的其他文献

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{{ truncateString('JOSEPH ELLIOTT BRAYDEN', 18)}}的其他基金

Ca Channels, TRP Channels & Vasomotor Function in Cerebral Arterioles
Ca 通道、TRP 通道
  • 批准号:
    7998811
  • 财政年份:
    2010
  • 资助金额:
    $ 36.58万
  • 项目类别:
Mechanisms of resistance artery contraction
阻力动脉收缩的机制
  • 批准号:
    7756578
  • 财政年份:
    1997
  • 资助金额:
    $ 36.58万
  • 项目类别:
MECHANISMS OF CEREBRAL RESISTANCE ARTERY CONTRACTION
脑阻力动脉收缩的机制
  • 批准号:
    2685534
  • 财政年份:
    1997
  • 资助金额:
    $ 36.58万
  • 项目类别:
Mechanism of Resistance Artery Contraction
动脉收缩阻力机制
  • 批准号:
    6621656
  • 财政年份:
    1997
  • 资助金额:
    $ 36.58万
  • 项目类别:
Mechanisms of resistance artery contraction
阻力动脉收缩的机制
  • 批准号:
    7342811
  • 财政年份:
    1997
  • 资助金额:
    $ 36.58万
  • 项目类别:
Mechanism of Resistance Artery Contraction
动脉收缩阻力机制
  • 批准号:
    6831661
  • 财政年份:
    1997
  • 资助金额:
    $ 36.58万
  • 项目类别:
MECHANISMS OF CEREBRAL RESISTANCE ARTERY CONTRACTION
脑阻力动脉收缩的机制
  • 批准号:
    2840176
  • 财政年份:
    1997
  • 资助金额:
    $ 36.58万
  • 项目类别:
Mechanisms of resistance artery contraction
阻力动脉收缩的机制
  • 批准号:
    7033535
  • 财政年份:
    1997
  • 资助金额:
    $ 36.58万
  • 项目类别:
Mechanism of Resistance Artery Contraction
动脉收缩阻力机制
  • 批准号:
    6688291
  • 财政年份:
    1997
  • 资助金额:
    $ 36.58万
  • 项目类别:
Mechanisms of resistance artery contraction
阻力动脉收缩的机制
  • 批准号:
    7172308
  • 财政年份:
    1997
  • 资助金额:
    $ 36.58万
  • 项目类别:

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ROLE OF CELL ADHESION IN BIOLOGICAL SIGNAL TRANSDUCTION
细胞粘附在生物信号转导中的作用
  • 批准号:
    6238317
  • 财政年份:
    1997
  • 资助金额:
    $ 36.58万
  • 项目类别:
ROLE OF CELL ADHESION IN BIOLOGICAL SIGNAL TRANSDUCTION
细胞粘附在生物信号转导中的作用
  • 批准号:
    5210031
  • 财政年份:
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    $ 36.58万
  • 项目类别:
CELL ADHESION IN BIOLOGICAL SIGNAL TRANSDUCTION
生物信号转导中的细胞粘附
  • 批准号:
    3732412
  • 财政年份:
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    $ 36.58万
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