Micromechanics of Traumatic Axonal Injury

轴突损伤是弥漫性脑损伤的一个标志，许多人认为它几乎是一种普遍性的损伤。 创伤性脑损伤的后果。最近的证据表明，无髓鞘轴突尤其 在DAI中易受损害。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何时发生钠通道蛋白分解 轻度脑损伤后，确定调节该通道蛋白降解的机制(S)，并评价 不同生物标记物评估这种形式的轴突损伤的有效性。我们的具体目标是： 目的1：测定钠离子通道机械激活的应变率敏感阈值 轴突牵拉损伤的体外实验，确定对即刻和持续性都有贡献的途径(S) 牵张引起的轴浆钙离子增加， 目的2：确定轴突牵拉后钠通道蛋白降解的阈值和时程。 评估这种蛋白分解是否由钙蛋白激活所介导，并与特定的牵张诱导的钙有关 途径，并评估是否可以减少蛋白质分解使用延迟治疗。 目的3：确定膜通透性延迟性增加的阈值和时间过程 轴索牵张损伤，检查这种通透性的变化是否对延迟治疗有反应，并测试是否 这种通透性的变化导致了在体外检测轴突损伤的生物标志物的可检测释放。 我们的总体假设是：(A)在轻度牵张损伤过程中发生了钠通道的机械激活 无髓鞘轴突，(B)钠通道蛋白水解酶是Calain介导的，(C)主要途径(S) 牵张后轴突持续钙升高是控制钠通道蛋白分解的关键靶点 轴突损伤后。 相关性：颅脑损伤患者的一种常见损伤类型是轴突肿胀和分离。 遍及大脑的许多区域。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，以及 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.