Molecular Mechanisms of Enhanced Contractility following Traumatic Brain Injury:

创伤性脑损伤后收缩性增强的分子机制：

• 批准号: 8133700
• 负责人: CHRISTIAN W KREIPKE
• 金额: $ 32.59万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-03-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133700
• 关键词: Address; Afghanistan; Anatomy; Behavior; Behavioral; Blood Vessels; Blood flow; Brain; Brain Edema; Cardiovascular Physiology; Cause of Death; Centers for Disease Control and Prevention (U.S.); Cerebral Edema; Cerebrovascular Circulation; Cerebrum; Child; Clinical; Clinical Trials; Cognitive; Cognitive deficits; Craniocerebral Trauma; Data; Diffuse Axonal Injury; Emotional; Endothelin A Receptor; Endothelin Receptor; Endothelin-1; Event; Exposure to; Financial cost; Grant; Histopathology; Impaired cognition; Indium; Injection of therapeutic agent; Injury; Intracranial Pressure; Iraq; Laboratories; Life; Magnetic Resonance Imaging; Marines; Mediating; Methods; Microcirculation; Military Personnel; Modeling; Molecular; Molecular Biology; Names; Neuronal Injury; Neurons; Outcome; Pathology; Patient Care; Pharmaceutical Preparations; Pharmacology; Phase; Physiology; Psychiatry; Publishing; Quality of life; Radiology Specialty; Rehabilitation therapy; Reporting; Research Personnel; Role; Sailor; Stroke; System; Techniques; Terrorism; Testing; Tissues; Translating; Translations; Traumatic Brain Injury; Vascular Smooth Muscle; Vasospasm; War; Woman; Work; authority; blood flow measurement; brain repair; calponin; cell injury; clinically relevant; cost; design; disability; effective therapy; experience; fighting; functional outcomes; improved; injured; men; neural circuit; novel; novel strategies; novel therapeutic intervention; public health relevance; relating to nervous system; research study; response; vasoconstriction; young adult

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.

描述(申请人提供)：据报道，创伤性脑损伤(TBI)是导致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，脑外伤可导致三种主要的病理改变：1)脑水肿，导致颅内压严重升高；2)弥漫性轴索损伤，导致认知和运动行为的神经回路中断；3)脑微循环改变，导致持续的低灌流状态和重要代谢产物向神经组织的不适当输送。针对前两种病理机制的临床试验已超过25项，但没有一项临床试验对脑外伤的治疗有效。因此，新的研究导致新的临床试验是必要的。到目前为止，还没有人启动针对第三种病理的临床试验，即脑外伤后的血管反应性障碍。本提案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，为继续进行临床试验提供了理论基础。虽然我们的实验室已经发表了大量关于内皮素-1在介导脑创伤后脑血管反应性改变中的作用的文章，但这种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。这项建议通过对ET-1系统和降钙素(CP)的药理学操作来解决这些问题，降钙素(CP)是血管反应性的关键元素，血管反应性的分子事件导致血管平滑肌收缩，从而导致血管收缩。这一设想的中心假设是：脑损伤导致内皮素-1介导的血管收缩增强和脑血流量减少，进而加重脑损伤所致的神经元损伤和认知障碍。 公共卫生相关性：创伤性脑损伤(TBI)是导致青少年和儿童死亡和残疾的主要原因。此外，它已被列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患者护理和康复费用。虽然脑外伤会导致三种主要的病理改变，包括弥漫性轴索损伤、脑水肿和脑实质低灌流，但这项建议通过研究低灌流背后的基本机制，探索了增加损伤后血流量的新方法。在这样做的过程中，这项建议中的实验旨在产生可以迅速转化为临床环境的结果，从而抵消目前暴露于脑外伤后可能出现的令人沮丧的结果。

项目成果

Differential effects of endothelin receptor A and B antagonism on behavioral outcome following traumatic brain injury.

内皮素受体 A 和 B 拮抗作用对创伤性脑损伤后行为结果的不同影响。

• DOI: 10.1179/016164111x12881719352499
• 发表时间: 2011
• 期刊: Neurological research
• 影响因子: 1.9
• 作者: Reynolds,ChristianA;Schafer,Steven;Pirooz,Ryan;Marinica,Alex;Chbib,Ali;Bedford,Christopher;Fronczak,Michael;Rafols,JoseA;Kuhn,Donald;Kreipke,ChristianW
• 通讯作者: Kreipke,ChristianW

Clazosentan, a novel endothelin A antagonist, improves cerebral blood flow and behavior after traumatic brain injury.

Clazosentan 是一种新型内皮素 A 拮抗剂，可改善脑外伤后的脑血流量和行为。

• DOI: 10.1179/016164111x12881719352570
• 发表时间: 2011
• 期刊: Neurological research
• 影响因子: 1.9
• 作者: Kreipke,ChristianW;Rafols,JoséA;Reynolds,ChristianA;Schafer,Steven;Marinica,Alex;Bedford,Christopher;Fronczak,Michael;Kuhn,Donald;Armstead,WilliamM
• 通讯作者: Armstead,WilliamM