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

创伤性脑损伤是一个严重的公共卫生问题。颅脑损伤后，老年患者的 与年轻患者相比，死亡率和功能预后更差。治疗中的另一个并发症 由于对脑外伤的性别差异缺乏明确的认识，导致脑外伤的发生。生物年龄和性别的影响 关于TBI的结果是一个重要但研究不足的领域，也是导致 在几个与脑损伤相关的临床试验中观察到的有限成功归因于它们未能解释关键的 性别和年龄相关的疾病表达的差异。考虑到这一知识差距，我们的主要目标是 建议进行一项临床前研究，重点研究年龄和性别对脑外伤的影响。其中最 颅脑损伤的破坏性临床症状是脑水肿的形成，导致颅内面积增加 损害脑血流和氧合的压力，并导致额外的缺血性损伤。 保持血脑屏障(BBB)的完整性，这是大脑的保护屏障，并预防 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)是预防和治疗脑血管源性水肿的关键。我们提出了一种新的范式 脑外伤后微血管高通透性的年龄和性别相关性变化，并评估是否存在 导致这种高通透性的炎症介导的信号机制与年龄和性别有关。 我们的首要目标是了解一个人的年龄和性别如何对血管产生不同的影响 通透性和导致脑损伤后脑水肿的形成，最终形成新的有效的 为所有年龄/性别的头部创伤患者提供治疗。在这项提案中，我们将调查年龄和性别 差异调控导致中性粒细胞活化的微血管通透性和分子通路 细胞外陷阱(NET)和NLRP3炎症小体信号导致血管高通透性，如下 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/性别对 Net/NLRP3炎症组中的微血管通透性、脑液动力学和脑外伤预后 依赖的态度。颅脑损伤后净形成增加促进NLRP3炎症小体- 介导的内皮紧密连接(TJ)破裂、高通透性和脑水肿形成的年龄 和性依赖的态度。我们的具体目标是：1)确定年龄和性别对微血管的影响 脑外伤后的高通透性；2)确定微血管高通透性的上游调节因素 颅脑损伤后年龄、性别的影响。提议的新颖、集成的方法利用了一种精炼的 并结合活体微循环显微成像、薄层切片建立相应的小鼠脑损伤模型 和紧密连接的细小断口电子显微镜，脑流体动力学和细胞和 分子生物学的方法。理解这些新颖的原理将有助于我们找到新的方法来治疗和 预防脑外伤患者未来的脑水肿，不分年龄和性别。

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.