Biomechanical Analysis of Traumatic Brain Injury Models

这是一项专注于创伤性脑损伤生物力学的拨款的修订竞争延续。在……里面 在接下来的应用中，我们研究了组织应变如何转化为海马体中的细胞应变，以及 继续关注NMDAR在海马区的机械敏感性及其作用 神经元死亡。广泛的、长期的目标是检查区域神经元群体是否 机械上易受伤害，以测试非突触和突触NMDAR是否有 不同的机械敏感性，并利用NMDAR机械敏感性的数据来评估两者的即刻 以及延迟治疗策略，以减少机械损伤后神经元的死亡。这样做的具体目的是 研究计划如下： 目的1：描述器官型海马区培养的局部微机械环境。 真实的、与损伤相关的活体变形。 目的2：测定突触外和突触NMDAR的机械激活阈值 重组NMDAR在HEK293t细胞和海马区器官培养中的表达。 目的3：研究机械敏感型NMDARs对JNK和ERK的激活和调控 这一信息旨在检查急性和延迟治疗策略，以减少机械治疗后细胞死亡 受伤。 我们的假设是：(A)在相同的组织拉伸水平上，齿状回和CAS中的神经元 经历比其他海马区更高的机械变形，(B)NMDAR是拉伸的 由于与细胞骨架的联系而敏感，(C)突触外NMDA受体的机械激活将 通过STEP影响JNK的激活，以及(D)ERK的激活将优先受 突触NMDARs，ERK信号的持续时间由STEP的活性介导。 相关性：这项工作将研究在创伤性脑损伤期间海马区神经元是如何受损的。 这项工作将集中在研究一种受体的机械激活，该受体在 记忆形成和细胞死亡。利用受体激活的信息，研究人员将开发出 并测试减少创伤性脑损伤后神经元死亡的治疗策略。

This is a revised competing continuation of a grant focusing on the biomechanics of traumatic brain injury. In this continuation application, we study how tissue strains translate to cellular strains in the hippocampus, and proceed to concentrate on the NMDA receptor (NMDAR) mechanosensitivity and its role in hippocampal neuronal death. The broad, long term objective is to examine if regional neuronal populations are 'mechanically vulnerable' and susceptible to injury, to test if extrasynpatic and synpatic NMDARs have different mechanosensitivity, and to use the data on NMDAR mechanosensitivity to evaluate both immediate and delayed treatment strategies to reduce neuronal death after mechanical injury. The specific aims of this research plan are as follows: Aim 1: To describe the local micromechanical environment in organotypic hippocampal cultures subjected to realistic, in vivo deformations associated with injury. Aim 2: To measure the mechanoactivation threshold for extrasynaptic and synaptic NMDAR using recombinant NMDAR expressed in HEK293t cells and organotypic hippocampal cultures. Aim 3: To examine the activation and control of both JNK and ERK from mechanosensitive NMDARs, using this information to examine acute and delayed treatment strategies for reducing cell death after mechanical injury. Our overlying hypotheses are (a) at the same level of tissue stretch, neurons in the dentate gyrus and CAS experience higher mechanical deformations than other hippocampal regions, (b) NMDARs are stretch sensitive due to linkages to the cytoskeleton, (c) the mechanoactivation of extrasynaptic NMDA receptors will influence the activation of JNK through STEP, and (d) ERK activation will be preferentially controlled by synaptic NMDARs, with the duration of ERK signaling mediated by the activity of STEP. Relevance: This work will study how neurons in the hippocampus are injured during traumatic brain injury. The work will concentrate on studying the mechanical activation of a receptor known to play a role in memory formation and cell death. Using the information of receptor activation, the investigators will develop and test treatment strategies to reduce neuronal death following traumatic brain injury.