Control of Vascular Cell Motility by CaMKII

CaMKII 对血管细胞运动的控制

基本信息

  • 批准号:
    8235852
  • 负责人:
  • 金额:
    $ 39.11万
  • 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:
    2010-03-15 至 2014-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Migration of vascular smooth muscle (VSM) cells occurs during development, wound healing, angiogenesis, and contributes to the progression of vascular disease. Published studies support a role for the ubiquitous multifunctional serine/threonine protein kinase, Ca2+/calmodulin-dependent protein kinase II (CaMKII in regulating VSM cell migration, but the mechanisms of CaMKII activation in this setting, and the relevant substrate targets and mechanisms underlying effects on migration, are unknown. Based on our published and preliminary studies we have hypothesized that localized leading edge activation of CaMKII42 regulates focal adhesion dynamics and acts as a positive feedback to promote VSM cell polarization and directional migration. In Aim 1 molecular/genetic approaches will be used to manipulate CaMKII42 expression and activity, and the consequences on directional persistence and velocity of individual migrating VSM cells determined. Fluorescence recovery after photobleaching (FRAP) analysis of GFP-tagged focal adhesion components will be used to assess CaMKII4-dependent regulation of focal adhesion dynamics. In Aim 2 biochemical and advanced fluorescence imaging approaches (confocal FRET and TIRF microscopy) will be used to test a potential mechanism involving a functional CaMKII42 interaction with the Src-family kinase, Fyn, in regulating focal adhesion protein dynamics. VSM cell migration is a property of "synthetic phenotype" cells that have not acquired, or have lost, differentiated contractile protein markers and function. We have determined that up-regulation of a CaMKII4 isoform (42 or 4C) contributes to VSM cell synthetic phenotype functions (proliferation, migration). Recent studies indicate up-regulation of certain Ca2+ conducting cation channels in the TRPC and STIM/Orai families in synthetic phenotype VSM cells is linked functionally to regulation of proliferation and migration. Based on this, in Aim 3 we molecular and fluorescence imaging approaches to test the hypothesis that STIM1/Orai1 mediated Ca2+ entry is functionally linked to leading edge CaMKII activation. In aim 4 we test the hypothesis that that expression of CaMKII4 isozymes and these Ca2+ channels are co-regulated as a function of VSM phenotype, conferring an integrated pathway for Ca2+-dependent regulation of VSM cell migration in vivo. Results of these novel studies are expected to provide insight into mechanisms by which Ca2+ signals regulate VSM cell migration and to provide a basis for understanding Ca2+-dependent regulation of migration in other cell types and processes such as myofibroblast-mediated wound healing or angiogenesis. Taken with recently published studies in heart and skeletal muscle, these studies in VSM suggest that CaMKII4 isoforms may be generally important in muscle remodeling in response to physiological or pathophysiological stressors. PUBLIC HEALTH RELEVANCE: By elucidating the functional consequences of CaMKII isoforms in response to vascular injury, these studies are expected to provide insights into mechanisms underlying vascular proliferative diseases including atherosclerosis and restenosis follow vascular surgery. Because Ca2+ signals and CaMKII are a ubiquitous regulatory system in all cells and tissues, the information derived from these studies can be reasonably expected to extend to other processes involving vascular cell motility such as myofibroblast-mediated wound healing or angiogenesis.
描述(由申请人提供):血管平滑肌(VSM)细胞的迁移在发育,伤口愈合,血管生成过程中发生,并有助于血管疾病的发展。已发表的研究支持无处不在的多功能丝氨酸/苏氨酸蛋白激酶,Ca2+/钙调蛋白依赖蛋白依赖性蛋白激酶II(调节VSM细胞迁移的CAMKII,但在这种情况下Camkii激活的机制,在这种情况下激活了相关的源头和机构的迁移和机构效应,并且在迁移范围内效果不明显。假设CAMKII42的局部前缘激活可以调节焦点粘附动力学,并作为促进VSM细胞极化和方向性迁移的正反馈。 GFP标记的焦点粘附成分将用于评估AIM 2生物化学和先进的荧光成像方法中的CAMKII4依赖性调节。动力学。 VSM细胞迁移是尚未获得或丢失的分化收缩蛋白标记和功能的“合成表型”细胞的特性。我们已经确定CAMKII4同工型(42或4C)的上调有助于VSM细胞合成表型功能(增殖,迁移)。最近的研究表明,在合成表型VSM细胞中,在TRPC和STIM/ORAI家族中某些Ca2+导电通道的上调在功能上与增殖和迁移的调节有关。基于此,在AIM 3中,我们分子和荧光成像方法测试了STIM1/ORAI1介导的Ca2+进入的假设在功能上与CAMKII的前缘激活有关。在AIM 4中,我们检验了以下假设:CAMKII4同工酶的表达和这些Ca2+通道的表达是VSM表型的函数共同调节的,从而赋予了Ca2+依赖性调节VSM细胞迁移的综合途径。预计这些新研究的结果将提供有关CA2+信号调节VSM细胞迁移的机制的洞察力,并为理解Ca2+依赖性依赖性调节的基础提供了其他细胞类型和过程中的迁移调节,例如肌成纤维细胞介导的伤口愈合或血管生成。通过最近发表的心脏和骨骼肌研究,这些研究中的这些研究表明,CAMKII4同工型通常在响应生理或病理生理应激源的肌肉重塑中很重要。 公共卫生相关性:通过阐明CAMKII同工型的功能后果,以应对血管损伤,这些研究有望提供对血管增生性疾病潜在机制的见解,包括动脉粥样硬化和再生一症,包括血管性手术。由于Ca2+信号和CAMKII是所有细胞和组织中普遍存在的调节系统,因此可以合理地期望从这些研究中得出的信息扩展到涉及血管细胞运动的其他过程,例如肌纤维细胞介导的伤口愈合或血管生成。

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)

暂无数据

数据更新时间:2024-06-01

HAROLD A SINGER的其他基金

Control of Vascular Cell Motility by CaMKII
CaMKII 对血管细胞运动的控制
  • 批准号:
    7899534
    7899534
  • 财政年份:
    2010
  • 资助金额:
    $ 39.11万
    $ 39.11万
  • 项目类别:
Control of Vascular Cell Motility by CaMKII
CaMKII 对血管细胞运动的控制
  • 批准号:
    8043594
    8043594
  • 财政年份:
    2010
  • 资助金额:
    $ 39.11万
    $ 39.11万
  • 项目类别:
Control of Vascular Cell Motility by CaMKII
CaMKII 对血管细胞运动的控制
  • 批准号:
    8424244
    8424244
  • 财政年份:
    2010
  • 资助金额:
    $ 39.11万
    $ 39.11万
  • 项目类别:
Calcium/Calmodulin Activated Kinases in Smooth Muscle
平滑肌中钙/钙调蛋白激活的激酶
  • 批准号:
    7822181
    7822181
  • 财政年份:
    2009
  • 资助金额:
    $ 39.11万
    $ 39.11万
  • 项目类别:
CALCIUM/CALMODULIN ACTIVATED KINIASES IN SMOOTH MUSCLE
平滑肌中钙/钙调蛋白激活的激酶
  • 批准号:
    6638340
    6638340
  • 财政年份:
    1994
  • 资助金额:
    $ 39.11万
    $ 39.11万
  • 项目类别:
CALCIUM/CALMODULIN ACTIVATED KINASES IN SMOOTH MUSCLE
平滑肌中钙/钙调蛋白激活的激酶
  • 批准号:
    2225510
    2225510
  • 财政年份:
    1994
  • 资助金额:
    $ 39.11万
    $ 39.11万
  • 项目类别:
Calcium/Calmodulin Activated Kinases in Smooth Muscle
平滑肌中钙/钙调蛋白激活的激酶
  • 批准号:
    6890456
    6890456
  • 财政年份:
    1994
  • 资助金额:
    $ 39.11万
    $ 39.11万
  • 项目类别:
CALCIUM/CALMODULIN ACTIVATED KINASES IN SMOOTH MUSCLE
平滑肌中钙/钙调蛋白激活的激酶
  • 批准号:
    2709135
    2709135
  • 财政年份:
    1994
  • 资助金额:
    $ 39.11万
    $ 39.11万
  • 项目类别:
Calcium/Calmodulin Activated Kinases in Smooth Muscle
平滑肌中钙/钙调蛋白激活的激酶
  • 批准号:
    8063208
    8063208
  • 财政年份:
    1994
  • 资助金额:
    $ 39.11万
    $ 39.11万
  • 项目类别:
Calcium/Calmodulin Activated Kinases in Smooth Muscle
平滑肌中钙/钙调蛋白激活的激酶
  • 批准号:
    8449739
    8449739
  • 财政年份:
    1994
  • 资助金额:
    $ 39.11万
    $ 39.11万
  • 项目类别:

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