Influence of Age and Sex on Cerebral Edema Formation Following Traumatic Brain Injury

创伤性脑损伤（TBI）是一个严重的公共卫生问题。TBI后，老年患者遭受更高的 与年轻患者相比，死亡率和功能结局更差。治疗中的另一个并发症 TBI的发生是由于缺乏对TBI性别差异的明确认识。生物学年龄和性别的影响 TBI的结果是一个重要但研究不足的研究领域，也是TBI的主要原因之一。 在几项TBI相关临床试验中观察到的有限成功归因于它们未能解释关键因素 疾病表达的性别和年龄相关差异。考虑到这一知识差距，我们的主要目标是 建议是进行一项临床前研究，重点是年龄和性别对TBI的影响。一个最 创伤性脑损伤的破坏性临床症状是脑水肿的形成，导致颅内出血增加。 压力，损害脑灌注和氧合，并有助于额外的缺血性损伤。 维持血脑屏障（BBB）的完整性，脑的保护屏障，并预防脑缺血。 液体和蛋白质从小血管渗漏到血管外空间（微血管 高通透性）对于预防和治疗脑血管源性水肿至关重要。我们提出了一个新的范例 TBI后微血管通透性的年龄和性别依赖性变化，并评估 导致这种高渗透性的炎症介导的信号传导机制是年龄和性别依赖性的。 我们的首要目标是了解个体的年龄和性别如何差异性地影响血管 并导致脑水肿形成后TBI，并最终开发新的和有效的 适用于所有年龄/性别的头部创伤患者。在本提案中，我们将调查年龄和性别 差异控制微血管通透性和导致神经元活化的分子途径 细胞外陷阱（NET）和NLRP 3炎症体信号传导导致血管通透性过高， TBI以及年龄和性别如何影响这一途径。我们的中心假设是，年龄/性别差异影响 NET/NLRP 3炎性小体中微血管通透性、脑流体动力学和TBI的结果， 依赖的方式。TBI后增加的NET形成促进NLRP 3炎性小体- 介导的内皮紧密连接（TJ）破坏，高通透性和脑水肿形成的年龄 性依赖的方式。我们的具体目标是：1）确定年龄和性别对微血管的影响 TBI后的高通透性; 2）确定微血管高通透性的上游调节因子 以及年龄和性别的影响。所提出的新颖的综合方法利用了一种改进的 并结合活体微循环显微成像、薄层切片 紧密连接的电镜观察、脑流体动力学分析、细胞和 分子生物学方法。理解这些新的原理将有助于我们找到新的治疗方法， 预防脑水肿的头部外伤患者在未来，无论他们的年龄和性别。

Traumatic brain injury (TBI) is a serious public health concern. After TBI, elderly patients suffer from higher mortality rate and worse functional outcome compared to young patients. A further complication in the treatment of TBI occurs due to lack of clear knowledge on sex differences in TBI. The influence of biological age and sex on the outcomes of TBI is an important but understudied area of research and one of the major reasons for the limited success observed in several TBI-related clinical trials is, attributed to their failure to account for critical sex and age-related differences in disease expression. Considering this gap in knowledge, the major goal of our proposal is to conduct a pre-clinical study that focuses on the influence of age and sex in TBI. One of the most devastating clinical symptoms of TBI is the formation of cerebral edema leading to an increase in intracranial pressure that impairs cerebral perfusion and oxygenation, and contributes to additional ischemic injuries. Maintaining integrity of the blood-brain barrier (BBB), the protective barrier of the brain, and the prevention of the leakage of fluid and proteins from small blood vessels to the extravascular space (microvascular hyperpermeability) are critical to preventing and treating brain vasogenic edema. We propose a novel paradigm of age and sex dependent changes in microvascular hyperpermeability following TBI, and evaluate if an inflammatory-mediated signaling mechanism responsible for this hyperpermeability is age and sex dependent. Our overarching goal is to understand how age and sex of an individual differentially influence vascular permeability and leading to cerebral edema formation following TBI and ultimately develop new and effective therapeutics for head trauma patients of all ages/sex. In this proposal, we will investigate how age and sex differentially control microvascular permeability and molecular pathways that lead to activation of Neutrophil Extracellular Traps (NET) and NLRP3 inflammasome signaling resulting in vascular hyperpermeability, following TBI and how age and sex influence this pathway. Our central hypothesis is that age/sex differentially influence microvascular permeability, cerebral fluid dynamics and outcomes of TBI, in an NET/NLRP3 inflammasome- dependent manner. Increased NET formation that occurs following TBI promotes NLRP3 inflammasome- mediated endothelial tight junction (TJ) breakdown, hyperpermeability and cerebral edema formation in an age and sex dependent manner. Our specific aims are to: 1) Determine the influence of age and sex on microvascular hyperpermeability following TBI; 2) Determine the upstream regulators of microvascular hyperpermeability following TBI and the influence of age and sex. The proposed novel, integrated approach capitalizes on a refined and relevant mouse model of TBI combined with intravital microscopic imaging of microcirculation, thin-section and feeze-fracture electron microscopy of tight junctions, analysis of cerebral fluid dynamics and cellular and molecular biology approaches. Understanding these novel principles will help us find new ways to treat and prevent cerebral edema in head trauma patients in the future, irrespective of their age and sex.