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会导致三种主要病理：1)脑水肿，导致颅内压急剧升高；2)弥漫性轴索损伤，导致认知和运动行为背后的神经回路中断；3)大脑微循环的改变，导致持续的低灌注状态和重要代谢物向神经组织的输送不当。针对前两种病理已经开展了超过25项临床试验，但没有一项对TBI的治疗有效。因此，有必要进行新的研究，从而进行新的临床试验。到目前为止，还没有人发起了针对第三种病理的临床试验，即创伤性脑损伤后的血管反应功能障碍。目前的建议为通过实施旨在改善脑外伤后脑血流量（CBF）和认知结果的新策略进行临床试验提供了基本原理。虽然我们的实验室已经发表了大量关于内皮素-1在TBI后介导脑血管反应性改变中的作用的文章，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。该建议通过对ET-1系统和钙钙蛋白（Cp）的药理学操作来解决这些问题，钙钙蛋白是血管反应性的关键因素-导致血管平滑肌收缩的分子事件，从而导致血管收缩。该建议的中心假设是：脑外伤引起内皮素-1介导的血管收缩增强和脑血流减少，这反过来又加剧了脑外伤引起的神经元损伤和认知缺陷。

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.