Micromechanics of Traumatic Axonal Injury

轴突损伤是弥漫性脑损伤的标志，并且被许多人认为是几乎普遍的脑损伤。 创伤性脑损伤的后果。最近的证据表明，无髓鞘轴突特别是 易受DAI损伤。在这个项目中，我们研究了轴突损伤的微观力学方面， 无髓鞘轴突我们的长期目标是研究轴突中钠通道蛋白水解何时发生 在轻度TBI后，确定调节该通道蛋白水解的机制，并评估 不同生物标志物的有效性来评估这种形式的轴突损伤。我们的具体目标是： 目的1：测定钠通道机械激活的应变率敏感阈值 体外轴突牵张损伤，确定有助于立即和持续的 牵张诱导的轴浆钙增加， 目的2：确定轴突牵张后钠通道蛋白水解的阈值和时程， 评估这种蛋白水解是否是由钙蛋白酶激活介导的，并与特定的牵张诱导的钙 途径，并评估是否可以使用延迟治疗减少蛋白水解。 目的3：确定膜通透性延迟增加的阈值和时程， 轴突拉伸损伤，检查这种渗透性的变化是否对延迟治疗有反应，并测试是否 这种渗透性变化导致可检测的“生物标志物”释放，用于体外检测轴突损伤。 我们的总体假设是：（a）钠通道机械激活发生在轻度牵张损伤期间， 无髓鞘轴突，（B）钠通道蛋白水解是钙蛋白酶介导的，（c） 拉伸后轴突中持续的钙升高是控制钠通道蛋白水解的关键目标 轴突损伤后。 相关性：头部受伤患者的一种常见损伤类型是轴突肿胀和断开 在大脑的许多区域。我们将研究这种损伤是如何发生的，评估我们是否可以治疗这种损伤， 将评估是否有特定的生物标志物可以作为轴突变性的预后指标。

Axonal damage is a hallmark of diffuse brain injuries, and is considered by many as a nearly universal consequence of traumatic brain injury. Recent evidence shows that unmyelinated axons are particularly vulnerable to damage in DAI. In this project, we study the mciromechanical aspects of axonal injury to unmyelinated axons. Our long term objective to study when sodium channel proteolysis occurs in axons after mild TBI, determine the mechanism(s) that regulate this channel proteolysis, and to evaluate the effectivenes of different biomarkers to evaluate this form of axonal damage. Our specific aims are to: Aim 1: To measure the strain rate sensitive threshold for sodium channel mechanoactivation following axonal stretch injury in vitro, determining the pathway(s) that contribute to both immediate and sustained stretch-induced increases in axoplasmic calcium, Aim 2: To determine the thresholds and timecourse of sodium channel proteolysis after axonal stretch, assess if this proteolysis is mediated by calpain activation and linked to a specific stretch-induced calcium pathway, and evaluate if the proteolysis can be reduced using delayed treatments. Aim 3: To determine the threshold and time course of a delayed increase in membrane permeability after axonal stretch injury, examine if this permeability changes is responsive to delayed treatments, and to test if this permeability change leads to a detectable release of 'biomarkers' for detecting axonal injury in vitro. Our overall hypotheses are that (a) sodium channel mechanoactivation occurs during mild stretch injury to unmyelinated axons, (b) sodium channel proteolysis is calpain mediated, (c) the primary pathway(s) for sustained calcium elevation in axons after stretch is a critical target in controlling sodium channel proteolysis after axonal injury. Relevance: One common type of injury in head injured patients is the swelling and disconnection of axons throughout many brain regions. We will study how this injury occurs, evaluate if we can treat this injury, and will assess if there specific biomarkers that can serve as prognostic indicators of axonal degeneration.