Molecular Mechanisms of Enhanced Contractility following Traumatic Brain Injury:

描述（由申请人提供）：据报道，创伤性脑损伤（TBI）是儿童和年轻人死亡和残疾的主要原因（CDC报告，2004年）。在多种后遗症中，TBI导致三种主要病理：1）脑水肿，其导致颅内压的临界升高，2）弥漫性轴突损伤，其导致认知和运动行为的神经回路的破坏，以及3）脑微循环的改变，其导致持续的低灌注状态和重要代谢物向神经组织的不适当递送。已经开发了针对前两种病理的超过25项临床试验，其中没有一项在治疗TBI方面有效。因此，有必要开展新的研究，开展新的临床试验。到目前为止，还没有人开始针对第三种病理学，即TBI后功能障碍性血管反应性的临床试验。本提案提供了通过实施旨在改善脑血流量（CBF）和TBI后认知结果的新策略进行临床试验的基本原理。虽然我们的实验室已经发表了大量关于内皮素-1介导TBI后脑血管反应性改变的作用，但这种血管反应性改变的细胞和分子机制仍有待阐明。此外，ET-1、血管反应性改变和功能结局之间的因果关系尚未确定。该提案通过ET-1系统和钙调蛋白（Cp）的药理学操作解决了这些问题，钙调蛋白是血管反应性的关键因素-导致血管平滑肌收缩并因此导致血管收缩的分子事件。该提议的中心假设是：TBI引起内皮素-1介导的血管收缩增强和CBF减少，这反过来又加剧了TBI诱导的神经元损伤和认知缺陷。 创伤性脑损伤（TBI）是青少年和儿童死亡和残疾的主要原因。此外，它被命名为反恐战争中的标志性伤害，一旦我们在伊拉克和阿富汗作战的男女士兵返回，预计将花费数百万美元的病人护理和康复费用。虽然TBI导致三种主要病理，包括弥漫性轴索损伤、脑水肿和脑实质的灌注不足，但该提案通过研究灌注不足背后的基本机制来研究增加损伤后血流量的新方法。在这样做时，本提案中的实验旨在产生可以快速转化为临床环境的结果，从而抵消暴露于TBI后当前潜在的令人沮丧的结果。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is reportedly the leading cause of death and disability among children and young adults (CDC Report, 2004). Among multiple sequelae, TBI results in three major pathologies: 1) cerebral edema which leads to a critical rise in intracranial pressure, 2) diffuse axonal injury which brings about disruption of neural circuits underlying cognitive and motoric behaviors, and 3) alterations in the brain's microcirculation that cause a persistent state of hypoperfusion and improper delivery of vital metabolites to neural tissue. Over 25 clinical trials aimed at the first two pathologies have been developed, none of which have been effective in the treatment for TBI. Therefore, novel studies leading to new clinical trials are necessary. To date no one has initiated a clinical trial addressing the third pathology, dysfunctional vascular reactivity following TBI. The present proposal provides rationale for proceeding towards a clinical trial by implementing novel strategies that aim to improve cerebral blood flow (CBF) and cognitive outcome following TBI. While our laboratory has published extensively on the role of endothelin-1 in mediating altered cerebral vascular reactivity after TBI, the cellular and molecular mechanism for this altered vasoreactivity remains to be elucidated. In addition the causal relationship between ET-1, altered vasoreactivity and functional outcome has not been established. This proposal addresses these issues by pharmacologic manipulation of the ET-1 system and calponin (Cp), a key element in vasoreactivity - the molecular events leading to vascular smooth muscle contractility and hence to vasoconstriction. The central hypothesis of this proposal is: TBI causes enhanced endothelin-1-mediated vasoconstriction and reduced CBF, which, in turn, exacerbates TBI-induced neuronal injury and cognitive deficits. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is the leading cause of death and disability amongst our youth and children. Further, it has been named as the signature injury in the War on Terrorism that, upon return of our men and women fighting in Iraq and Afghanistan, is projected to cost millions in patient care and rehabilitation costs. While TBI results in three major pathologies, including diffuse axonal injury, brain edema, and hypoperfusion of the brain's parenchyma, this proposal investigates novel methods to increase blood flow after injury by investigating the fundamental mechanism behind hypoperfusion. In doing so, the experiments in this proposal are designed to yield results that can quickly be translated into the clinical setting, thus off-setting the current potentially dismal outcome following exposure to TBI.