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Traumatic brain injury: early mechanosensitive events in astrocytes

创伤性脑损伤：星形胶质细胞的早期机械敏感事件

基本信息

批准号：
8722056
负责人：
ZONGLU S HUA
金额：
$ 19.69万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8722056
关键词：
Accidents Actinin Address Adult Anatomy Astrocytes Biological Biological Assay Blast Cell Brain Brain Injuries Cardiovascular system Cell Volumes Cell physiology Cells Cellular Stress Cellular Structures Complex Coupled Coupling Cytoskeletal Proteins Cytoskeleton Dependence Disease Etiology Event Fluorescence Resonance Energy Transfer Fluorescent Probes Focal Adhesions Frequencies Glial Fibrillary Acidic Protein Global Change Homeostasis Hour Injury Lead Link Liquid substance Maintenance Measurable Measures Mechanical Stress Mechanics Medicine Metabolic Microfluidics Molecular Neurons Neurotransmitters Pharmaceutical Preparations Pharmacotherapy Physiologic pulse Play Preventive Process Property Proteins Research Role Sampling Secondary to Solutions Spectrin Stimulus Stress Structure Subcellular Anatomy Synapses Talin Testing Therapeutic Therapeutic Agents Time Traumatic Brain Injury Variant Veterans Vinculin brain cell cell injury in vivo inhibitor/antagonist paxillin physical property pressure prevent public health relevance research study response sensor shear stress tissue culture

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is brain damage resulting from an external mechanical force, such as blast or crashes. Our current understanding of TBI is derived mainly from in vivo studies that show measurable biological effects on cells sampled after TBI. Little is known about the primary mechanical stresses in brain cells during damaging stimuli, and how they are transduced into cellular and molecular events involved in TBI. This proposal aims to examine what stimulus properties are most critical to cell injury and how the mechanical stimulus is coupled to secondary cellular processes. We will use tissue cultured adult astrocytes in a microfluidic chamber driven by a fast pressure servo to generate time dependent fluid shear that can be made to emulate shear stress from a blast. We will directly measure the stresses in specific cytoskeletal proteins using genetically encoded fluorescent stress sensors. The research has two specific aims. Aim 1 identifies physical properties of the stimulus that lead to long term alterations. By measuring the time course of stresses in specific cytoskeletal proteins using shockwaves of various amplitude, rise time, and frequency, we will determine the parameters that lead to irreversible deformation. This irreversibility will be determined by investigating changes in anatomy and stress distribution. Aim 2 investigates the cells' response during and immediately after mechanical insult to determine how mechanical stimulus alters cell homeostasis. For this we will measure the time dependent changes of intracellular Ca2+ and cell volume. These properties will be measured simultaneously with cellular stress to determine causality. We will further test the role of mechanosensitive channels for passing Ca2+ using specific inhibitor, GsMTx4, and explore whether pre-administration of GsMTx4 might be used as a preventive therapy.

描述（由申请人提供）：创伤性脑损伤（TBI）是由外部机械力（如爆炸或碰撞）引起的脑损伤。我们目前对TBI的理解主要来自体内研究，这些研究显示了TBI后对细胞采样的可测量的生物学效应。在损伤性刺激过程中，脑细胞中的主要机械应力，以及它们如何被转换成TBI所涉及的细胞和分子事件，目前知之甚少。该建议旨在研究什么样的刺激特性对细胞损伤最关键，以及机械刺激如何与次级细胞过程耦合。我们将在由快速压力伺服驱动的微流体室中使用组织培养的成年星形胶质细胞来产生时间依赖性流体剪切，该剪切可以模拟来自爆炸的剪切应力。我们将使用基因编码的荧光应力传感器直接测量特定细胞骨架蛋白中的应力。这项研究有两个具体目标。目标1确定导致长期改变的刺激的物理特性。通过使用不同振幅、上升时间和频率的冲击波测量特定细胞骨架蛋白中的应力的时间过程，我们将确定导致不可逆变形的参数。这种不可逆性将通过研究解剖结构和应力分布的变化来确定。目的2研究机械损伤过程中和损伤后细胞的反应，以确定机械刺激如何改变细胞的稳态。为此，我们将测量细胞内Ca2+和细胞体积的时间依赖性变化。这些特性将与细胞应激同时测量，以确定因果关系。我们将使用特异性抑制剂GsMTx4进一步测试机械敏感性通道传递Ca 2+的作用，并探索预先施用GsMTx4是否可用作预防性治疗。