Mechanisms of mechanical force evoked Ca2+ influx in developing neurons

机械力在发育中的神经元中引起 Ca2+ 流入的机制

基本信息

批准号：
8606120
负责人：
Patrick C Kerstein
金额：
$ 3.37万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-07 至 2014-12-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8606120
关键词：
Acute Adhesions Adult Axon Behavior Biological Assay Brain Calcium Calcium Channel Calcium Signaling Calpain Cations Cell membrane Cells Chemicals Cleaved cell Cognition Disorders Cues Data Dendrites Detection Development Disease Dominant-Negative Mutation Embryo Environment Environmental Risk Factor Family Figs - dietary Focal Adhesion Kinase 1 Frequencies Genes Growth Growth Cones Homo Human Image Individual Inflammatory Ions Location Maps Measures Mechanical Stimulation Mechanics Mediating Mental Retardation Mental disorders Molecular Morphogenesis Mutate Mutation Natural regeneration Nerve Nervous system structure Neuraxis Neurites Neuroglia Neuronal Injury Neurons Nociceptive Stimulus Peptide Hydrolases Peptides Peripheral Nervous System Physiology Proteins Proteolysis Regulation Research Role Sensory Signal Transduction Site Spinal Stimulus Synapses Talin Temperature Testing Therapeutic Intervention Tissues Variant Xenopus axon guidance axon regeneration base cell motility chemical function cognitive function design developmental disease flexibility knock-down loss of function migration mutant nervous system development neurodevelopment painful neuropathy paxillin pressure public health relevance receptor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The development of the nervous system requires the proper differentiation, migration and morphogenesis of neurons. The morphogenesis of individual neurons and the assembly of the trillions of neuronal circuits that define the human nervous system occur through guided extension of axons and dendrites. The objective of this research is to better understand the calcium channels and downstream effector mechanisms that are responsible for the proper wiring of the brain. For this we must understand how nerve growth cones detect, integrate and respond to soluble, as well as cell- and substratum- associated guidance molecules in their environment. Mutations in genes involved in the detection and transduction of axon guidance information into directed neurite outgrowth are responsible for many deficits in cognitive function, including autisms, dyslexias, psychological disorders and mental retardations. Environmental factors that guide axons often stimulate intracellular calcium changes within growth cones. Interestingly, both growth promoting and inhibiting axon guidance cues have been shown to require intracellular calcium fluctuations. It is unclear how this simple ion can mediate distinct and even opposite effects on growth cone behavior, but many studies suggest that the frequency, amplitude and distribution of local calcium signals within growth cones determine the downstream effector mechanisms activated. Recent evidence suggests that the specific channel types involved in calcium influx or release from stores determines the effect on growth cone motility. This proposal will test the role of distinct transient receptor potential (TRP) channels on growth cone physiology and motility. TRP channels are plasma membrane cation channels composed of four subunits that are activated by diverse chemical and mechanical stimuli. Aim 1 uses gain- and loss-of-function approaches to determine which subunits form mechanically gated channels by testing how these channels control axon outgrowth and guidance. As our preliminary data shows calpain activity is tightly regulated by mechanically induced calcium influx. In Aim 2 we will investigate the molecular substrates of calpain proteolysis important for adhesion turnover and axon guidance. A better understanding of the molecular mechanisms through which calcium exerts such varied effects on growth cone motility will support treatment strategies for developmental disorders and neuronal injuries.

描述（由申请人提供）：神经系统的发展需要适当的分化，迁移和形态发生。单个神经元的形态发生以及定义人类神经系统的数万亿个神经元电路的组装，这是通过轴突和树突的引导延伸而发生的。这项研究的目的是更好地了解负责大脑正确接线的钙通道和下游效应器机制。为此，我们必须了解神经生长锥如何在其环境中检测，整合和响应可溶性，以及细胞和底层相关的指导分子。涉及轴突引导信息中涉及和转导的基因突变中，导致了许多认知功能的缺陷，包括自闭症，阅读障碍，心理疾病和心理障碍。引导轴突的环境因素通常会刺激生长锥内的细胞内钙变化。有趣的是，促进和抑制轴突引导提示都需要细胞内钙波动。目前尚不清楚这种简单的离子如何介导对生长锥行为的不同甚至相反的影响，但是许多研究表明，生长锥体内局部钙信号的频率，幅度和分布决定了激活下游效应器机制。最近的证据表明，涉及钙涌入或从商店释放的特定通道类型决定了对生长锥运动的影响。该建议将测试不同瞬态受体电位（TRP）通道对生长锥生理和运动性的作用。 TRP通道是质膜阳离子通道，由四个由多种化学和机械刺激激活的亚基组成。 AIM 1使用获得功能和功能丧失方法来确定哪些亚基通过测试这些通道如何控制轴突的生长和指导来形成机械门控通道。由于我们的初步数据表明，钙蛋白酶活性受到机械诱导的钙涌入的严格调节。在AIM 2中，我们将研究Calpain蛋白水解的分子底物对于粘附更新和轴突引导很重要。更好地理解钙对生长锥运动的各种影响的分子机制将支持发育障碍和神经元损伤的治疗策略。