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

年龄和性别对脑外伤后脑水肿形成的影响

基本信息

批准号：
10617193
负责人：
Binu Tharakan
金额：
$ 10.65万
依托单位：
MOREHOUSE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-05 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617193
关键词：
Address Affect Age Aging Area Biological Blood Blood - brain barrier anatomy Blood Vessels Blood brain barrier dysfunction Brain Brain Edema Cellular biology Cerebral Edema Cerebrum Cessation of life Clinical Clinical Trials Complication Craniocerebral Trauma Cytoplasmic Granules DNA Data Disease Economic Burden Elderly Electron Microscopy Endothelium Enzymes Estrogens Extravasation Failure Female Fracture Freeze Fracturing Functional Magnetic Resonance Imaging Functional disorder Future Genetic Goals Histones Impairment Incidence Individual Inflammasome Inflammatory Intracranial Pressure Knockout Mice Knowledge Liquid substance Mediating Microcirculation Microtomy Microvascular Permeability Molecular Molecular Biology Mus Neutrophil Activation Outcome Pathway interactions Patients Peptides Perfusion Permeability Persons Population Prevention Protein-arginine deiminase Proteins Public Health Research Severities Sex Differences Signal Transduction Societies Symptoms TBI Patients TBI treatment Testing Tight Junctions Trauma patient Traumatic Brain Injury Vascular Permeabilities Vasogenic Brain Edema Vertebral column age group age related aged biological sex cerebral microvasculature cytokine effective therapy extracellular functional outcomes inhibitor insight intravital imaging ischemic injury mRNA Expression male microscopic imaging middle age mortality mouse model neglect neutrophil novel older patient pharmacologic preclinical study prevent response sex success therapeutically effective

项目摘要

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.

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痛苦与年轻患者相比，死亡率和功能结果更差。治疗中的进一步并发症 TBI 的发生是由于缺乏对 TBI 性别差异的明确认识。生理年龄和性别的影响 TBI 的结果是一个重要但尚未得到充分研究的研究领域，也是造成这种情况的主要原因之一。在几项与 TBI 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因素疾病表现的性别和年龄相关差异。考虑到这种知识差距，我们的主要目标建议进行一项临床前研究，重点关注年龄和性别对 TBI 的影响。最有之一 TBI 的破坏性临床症状是脑水肿的形成，导致颅内压增加压力会损害脑灌注和氧合，并导致额外的缺血性损伤。维持大脑保护屏障——血脑屏障（BBB）的完整性，并预防液体和蛋白质从小血管渗漏到血管外空间（微血管）通透性过高）对于预防和治疗脑血管源性水肿至关重要。我们提出了一种新颖的范式 TBI 后微血管通透性过高的年龄和性别依赖性变化，并评估是否导致这种通透性过高的炎症介导的信号传导机制与年龄和性别有关。我们的首要目标是了解个体的年龄和性别如何对血管产生不同的影响渗透性并导致 TBI 后脑水肿形成，最终开发新的有效方法适用于所有年龄/性别的头部创伤患者的治疗方法。在本提案中，我们将调查年龄和性别如何差异性地控制微血管通透性和导致中性粒细胞激活的分子途径细胞外陷阱 (NET) 和 NLRP3 炎性体信号传导导致血管通透性过高，如下 TBI 以及年龄和性别如何影响该途径。我们的中心假设是年龄/性别对 NET/NLRP3 炎症小体中的微血管通透性、脑液动力学和 TBI 的结果依赖方式。 TBI 后发生的 NET 形成增加会促进 NLRP3 炎症小体介导的内皮紧密连接（TJ）破坏、通透性过高和不同年龄阶段的脑水肿形成和性别依赖方式。我们的具体目标是： 1）确定年龄和性别对微血管的影响 TBI 后渗透性过高； 2）确定微血管通透性过高的上游调节因子 TBI 后以及年龄和性别的影响。所提出的新颖的综合方法利用了精致的及相关TBI小鼠模型结合活体微循环显微成像、薄片和紧密连接的断裂电子显微镜，脑流体动力学和细胞和细胞的分析分子生物学方法。了解这些新颖的原理将帮助我们找到新的治疗方法和预防头部外伤患者未来出现脑水肿，无论其年龄和性别如何。