Gap Junctions in Vascular Smooth Muscle: Growth Control

血管平滑肌的间隙连接:生长控制

基本信息

  • 批准号:
    8209153
  • 负责人:
  • 金额:
    $ 37.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1997
  • 资助国家:
    美国
  • 起止时间:
    1997-07-15 至 2014-11-30
  • 项目状态:
    已结题

项目摘要

Project Description The long-term goals of this research are: 1) to understand the molecular mechanisms that govern the permeability and growth suppressive properties of vascular cell gap junctions and 2) to develop from that knowledge the rationale for gene therapies that target connexin expression in endothelial cells with the goal of limiting susceptibility to and facilitating recovery from ischemic injury. Three gap junction proteins are commonly expressed in vascular cells, connexin (Cx) 37, Cx40 and Cx43; in the endothelium Cx37 and Cx40 normally predominate, but during vasculogenesis and with stress, injury and disease, Cx37 is down-regulated and Cx43 up-regulated. The consequences of this change in expression on the vessel's ability to form new vessels and to maintain vessel functions during vascular remodeling remain uncertain. In our previous studies, we demonstrated that these connexins form gap junction channels with vastly different permselective and growth suppressive properties that are regulated by growth factor activated signaling cascades in a connexin- specific manner. In the current proposal we hypothesize that connexin-specific, phosphorylation-dependent regulation of junctional permselectivity provides vascular cells a strategy for maintaining coordinated contraction/relaxation functions of vessels while simultaneously supporting the proliferative response of cells therein. We address this hypothesis in Aim 1 by examining the mechanistic basis for how phosphorylation events in the carboxyl terminal domain (CT) lead to altered permselective properties of the associated pore domain. In aim 2 we extend the observations of Aim 1 and determine whether the growth suppressive properties of these connexins rely on their permselective properties and/or their direct interactions with proteins involved in cell cycle control and progression. These growth studies make use of Cx-deficient cell lines, endothelial cells isolated from wild type or Cx37 deficient mice, and an in vivo hindlimb ischemic injury model, asking whether Cx37 works in conjunction with or in opposition to Cx43 to regulate the angiogenic response induced by injury while preserving junctional permselective properties. A combination of electrophysiology and fluorescence microscopy will be used to quantify the permselective properties of junctions and molecular approaches will be used to identify essential regions/sites of interaction between connexin domains and between connexins and elements of the cell cycle machinery. Isolated endothelial cells and an in vivo ischemia model will be used to determine the benefit of connexin expression or silencing to the extent and speed of vascular remodeling following injury. Our studies can be expected to lend new insights on the mechanistic basis for phosphorylation-dependent regulation of the permeability and growth suppressive functions of the vascular connexins and to the possible use of gene therapy to manipulate connexin expression in the endothelium to maximize/minimize angiogenesis, as appropriate, in settings of vascular injury and disease.
项目描述

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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JANIS M BURT其他文献

JANIS M BURT的其他文献

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{{ truncateString('JANIS M BURT', 18)}}的其他基金

Phosphorylation and gating of cardiac connexin channels
心脏连接蛋白通道的磷酸化和门控
  • 批准号:
    9078759
  • 财政年份:
    2016
  • 资助金额:
    $ 37.88万
  • 项目类别:
Role of Connexin47 mutations in primary lymphedema
Connexin47 突变在原发性淋巴水肿中的作用
  • 批准号:
    8831729
  • 财政年份:
    2014
  • 资助金额:
    $ 37.88万
  • 项目类别:
Role of Connexin47 mutations in primary lymphedema
Connexin47 突变在原发性淋巴水肿中的作用
  • 批准号:
    8677486
  • 财政年份:
    2014
  • 资助金额:
    $ 37.88万
  • 项目类别:
Role of Gap Junctions in Blood Vessel Assembly
间隙连接在血管组装中的作用
  • 批准号:
    8267618
  • 财政年份:
    2009
  • 资助金额:
    $ 37.88万
  • 项目类别:
Role of Gap Junctions in Blood Vessel Assembly
间隙连接在血管组装中的作用
  • 批准号:
    7901514
  • 财政年份:
    2009
  • 资助金额:
    $ 37.88万
  • 项目类别:
Role of Gap Junctions in Blood Vessel Assembly
间隙连接在血管组装中的作用
  • 批准号:
    7750472
  • 财政年份:
    2009
  • 资助金额:
    $ 37.88万
  • 项目类别:
Role of Gap Junctions in Blood Vessel Assembly
间隙连接在血管组装中的作用
  • 批准号:
    8452686
  • 财政年份:
    2009
  • 资助金额:
    $ 37.88万
  • 项目类别:
GAP JUNCTIONS IN VASCULAR SMOOTH MUSCLE--GROWTH CONTROL
血管平滑肌的间隙连接——生长控制
  • 批准号:
    6030845
  • 财政年份:
    1997
  • 资助金额:
    $ 37.88万
  • 项目类别:
Gap junctions in Vascular Smooth Muscle: growth control
血管平滑肌的间隙连接:生长控制
  • 批准号:
    7039119
  • 财政年份:
    1997
  • 资助金额:
    $ 37.88万
  • 项目类别:
Gap junctions in Vascular Smooth Muscle: growth control
血管平滑肌的间隙连接:生长控制
  • 批准号:
    6929542
  • 财政年份:
    1997
  • 资助金额:
    $ 37.88万
  • 项目类别:

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