Directed growth cone migration by calcium signals

通过钙信号定向生长锥迁移

基本信息

  • 批准号:
    7451477
  • 负责人:
  • 金额:
    $ 30.52万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-09-15 至 2012-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The cell's ability to sense the environment and to determine the direction and proximity of an extracellular stimulus, followed by correct movement, is fundamental not only for neural development (e.g. neuronal migration and growth cone guidance) but also for immunity, angiogenesis, wound healing, and embryogenesis. Directional cell movement is also crucial for many pathological events, especially cancer-cell metastasis. Therefore, a better understanding of the cellular mechanisms that underlie the directional responses of cells to extracellular stimuli would constitute a major advance of our basic knowledge on directional cell motility and could provide the foundation for developing strategies and treatments for many illnesses. The proposed study will use nerve growth cones as the model to study the spatiotemporal Ca2+ signaling mechanisms underlying directional motility in response to extracellular cues. Calcium is a key second messenger that regulates a variety of cell motility, including directed cell migration. It has been established that Ca2+ mediates growth cone responses to guidance cues, including attractive and repulsive turning responses. Recent studies indicate that different, localized Ca2+ signals elicit a balancing act on the activity of calcium-calmodulin- dependent kinase II (CaMKII) and Calcineurin (CaN) phosphatase to control the attractive and repulsive turning of the growth cone. This application aims to further evaluate the Ca2+ mechanisms that control bidirectional growth cone steering in response to guidance cues. Three specific aims are proposed: (1) to examine the spatiotemporal patterns of cytosolic Ca2+ signals and their role in controlling growth cone steering, (2) to investigate the downstream mechanisms that sense various Ca2+ signals to control growth cone turning, (3) to test the hypothesis that FAK/Src links Ca2+ signaling to tyrosine phosphorylation in growth cone guidance. The proposed studies will take advantage of our rigorous assays of growth cone turning and a combination of high-resolution digital imaging, photoactivation of caged compounds, and molecular manipulation of signaling components. In particular, direct manipulation of intracellular Ca2+ concentrations by focal laser-induced photolysis (FLIP) of caged Ca2+ will be extensively used for dissecting the signaling components. Together, these experiments represent a comprehensive study that aims to understand the Ca2+ signaling mechanisms underlying growth cone motility and guidance. The long-term goal is to understand the molecular and cellular mechanisms that allow axonal growth cones to navigate through complex extracellular spaces for establishing intricate connections. Results from this study will not only advance our knowledge of molecular mechanisms underlying precise neuronal wiring during brain development and recovery, but also provide important insights into the cellular mechanisms underlying directional sensing of migrating cells during important biological responses such as chemotaxis of leukocytes during inflammatory response. PUBLIC HEALTH RELEVANCE: The cell's ability to sense the environment and to determine the direction and proximity of an extracellular stimulus, followed by correct movement, is fundamental not only for neural development (e.g. neuronal migration and growth cone guidance) but also for immunity, angiogenesis, wound healing, and embryogenesis. Directional cell movement is also crucial for many pathological events, especially cancer-cell metastasis. Therefore, a better understanding of the cellular mechanisms that underlie the directional responses of cells to extracellular stimuli would constitute a major advance of our basic knowledge on directional cell motility and could provide the foundation for developing strategies and treatments for many illnesses. The proposed study will use nerve growth cones as the model to study the spatiotemporal Ca2+ signaling mechanisms underlying directional motility in response to extracellular cues. The results from this set of studies will provide significant insights into the cellular mechanisms of growth cone pathfinding, as well as of directed cell movement in many physiological and pathological events. Therefore the work is directly relevant to public health.
描述(由申请人提供):细胞感知环境并确定细胞外刺激的方向和邻近的能力,然后进行正确的运动,不仅是神经发育(例如神经元迁移和生长锥引导)的基础,而且对于免疫,血管生成,伤口愈合和胚胎生成。方向细胞运动对于许多病理事件,尤其是癌细胞转移也至关重要。因此,更好地理解细胞对细胞外刺激的定向反应的基础的细胞机制将构成我们对方向细胞运动的基本知识的重大进步,并可以为制定许多疾病的策略和治疗奠定基础。拟议的研究将使用神经生长锥作为模型,以研究响应细胞外提示的方向运动的时空CA2+信号传导机制。钙是调节各种细胞运动的关键第二信使,包括定向细胞迁移。已经确定CA2+介导了对指导线索的增长锥反应,包括有吸引力的和排斥的转弯反应。最近的研究表明,不同的局部Ca2+信号引起了对钙 - 钙调蛋白依赖性激酶II(CAMKII)和钙调蛋白(CAN)磷酸酶的活性的平衡行为,以控制生长锥的有吸引力和排斥的转向。该应用程序旨在进一步评估控制双向生长锥转向的CA2+机制,以响应指导提示。 Three specific aims are proposed: (1) to examine the spatiotemporal patterns of cytosolic Ca2+ signals and their role in controlling growth cone steering, (2) to investigate the downstream mechanisms that sense various Ca2+ signals to control growth cone turning, (3) to test the hypothesis that FAK/Src links Ca2+ signaling to tyrosine phosphorylation in growth cone guidance.拟议的研究将利用我们严格的生长锥转弯的测定法以及高分辨率数字成像,笼子化合物的光活化以及信号成分的分子操作的组合。特别是,将通过斑点激光诱导的光解(FLIP)直接操纵细胞内Ca2+浓度,将广泛用于解剖信号传导成分。这些实验共同代表了一项综合研究,旨在了解生长锥运动和指导的CA2+信号传导机制。长期目标是了解允许轴突生长锥的分子和细胞机制,可以通过复杂的细胞外空间导航,以建立复杂的连接。这项研究的结果不仅将提高我们对脑发育和恢复过程中精确神经元接线的分子机制的了解,而且还提供了对重要生物学反应期间迁移细胞的细胞机制的重要见解,例如炎症反应期间白血细胞的化学量。公共卫生相关性:细胞感知环境并确定细胞外刺激的方向和接近的能力,其次是正确的运动,不仅对神经发育(例如神经元迁移和生长锥指导)是基本的,而且对于免疫,血管生成,伤口愈合,愈合和胚胎发生。方向细胞运动对于许多病理事件,尤其是癌细胞转移也至关重要。因此,更好地理解细胞对细胞外刺激的定向反应的基础的细胞机制将构成我们对方向细胞运动的基本知识的重大进步,并可以为制定许多疾病的策略和治疗奠定基础。拟议的研究将使用神经生长锥作为模型,以研究响应细胞外提示的方向运动的时空CA2+信号传导机制。这组研究的结果将为许多生理和病理事件中的生长锥探路和定向细胞运动的细胞机制提供重要的见解。因此,这项工作与公共卫生直接相关。

项目成果

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James Q Zheng其他文献

James Q Zheng的其他文献

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{{ truncateString('James Q Zheng', 18)}}的其他基金

Fascin in brain development and function
肌成束蛋白在大脑发育和功能中的作用
  • 批准号:
    10676626
  • 财政年份:
    2023
  • 资助金额:
    $ 30.52万
  • 项目类别:
Actin Regulation of Dendritic Spine Development and Plasticity
树突棘发育和可塑性的肌动蛋白调节
  • 批准号:
    10608784
  • 财政年份:
    2023
  • 资助金额:
    $ 30.52万
  • 项目类别:
Actin Mechanisms of Postsynaptic Structure and Function
突触后结构和功能的肌动蛋白机制
  • 批准号:
    8888282
  • 财政年份:
    2015
  • 资助金额:
    $ 30.52万
  • 项目类别:
Actin Mechanisms of Postsynaptic Structure and Function
突触后结构和功能的肌动蛋白机制
  • 批准号:
    8998069
  • 财政年份:
    2015
  • 资助金额:
    $ 30.52万
  • 项目类别:
Activity-dependent translation and release of BDNF
BDNF 的活动依赖性翻译和释放
  • 批准号:
    8457027
  • 财政年份:
    2012
  • 资助金额:
    $ 30.52万
  • 项目类别:
Activity-dependent translation and release of BDNF
BDNF 的活动依赖性翻译和释放
  • 批准号:
    8299681
  • 财政年份:
    2012
  • 资助金额:
    $ 30.52万
  • 项目类别:
Directed growth cone migration by calcium signals
通过钙信号定向生长锥迁移
  • 批准号:
    7932519
  • 财政年份:
    2009
  • 资助金额:
    $ 30.52万
  • 项目类别:
Directed growth cone migration by calcium signals
通过钙信号定向生长锥迁移
  • 批准号:
    7684613
  • 财政年份:
    2008
  • 资助金额:
    $ 30.52万
  • 项目类别:
Directed growth cone migration by calcium signals
通过钙信号定向生长锥迁移
  • 批准号:
    8137079
  • 财政年份:
    2008
  • 资助金额:
    $ 30.52万
  • 项目类别:
Directed growth cone migration by calcium signals
通过钙信号定向生长锥迁移
  • 批准号:
    7905754
  • 财政年份:
    2008
  • 资助金额:
    $ 30.52万
  • 项目类别:

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