Acute Respiratory Distress Syndrome after Isolated Traumatic Brain Injury: Platelet Biology, Endothelial Activation, and Mechanical Ventilation

项目摘要/摘要 这是为卡洛琳·亨德里克森医生申请K23奖项的申请，她是一名肺部和重症监护内科医生， 加州大学旧金山分校。亨德里克森博士正在确立自己作为一名年轻研究员的地位 以患者为中心的急性呼吸窘迫综合征(ARDS)生物学研究 颅脑损伤后急性呼吸窘迫综合征的发病机制这项K23奖项将为亨德里克森博士提供 实现以下目标所需的支持：(1)成为临床和翻译专家 研究人员对创伤后ARDS的研究；(2)研究脑外伤后ARDS的生物学机制 机械通气所致的血小板生物学、内皮激活和肺损伤；(3)实施 高级复杂观测数据分析，包括机器学习；(4)开发独立的 翻译研究生涯。亨德里克森博士实现这些目标的计划得到了一个多学科的支持 由专家组成的指导团队。她的主要导师迈克尔·马泰博士在翻译方面拥有丰富的经验 ARDS研究和早期调查人员的职业发展。亨德里克森博士将与四名 合作导师：米切尔·科恩博士，研究创伤后凝血的翻译研究员，艾伦博士 哈伯德，专门从事因果推理的生物统计学家，杰弗里·曼利博士，神经外科医生和 脑损伤研究的研究员马克·鲁尼博士以及血小板生物学和肺损伤专家马克·鲁尼博士。 颅脑损伤后ARDS的发展是常见的，并与较差的神经预后相关。这个 颅脑损伤后ARDS的生物学机制尚不清楚。这项提议的中心假设是 脑外伤后ARDS的风险是通过激活的血管内皮细胞和血小板以及 使用大潮气量的非保护性机械通风策略。亨德里克森博士将调查 利用之前收集的数据和正在进行的观察队列的血浆，这些因果路径 学习。在同一个队列中，她将前瞻性地收集生物标本，详细的机械通气数据， 和肺部超声图像。这一建议代表了一种研究创伤性脑损伤后ARDS的创新方法 使用仔细判断的曝光率和结果。亨德里克森博士将测试血浆生物标记物 内皮激活、血管通透性和炎症(目标1)和血小板功能、激活和 聚集(AIM 2)与脑损伤后ARDS相关。她会收集肺部超声图像，并经常 机械通风数据，包括潮气量和高原压力。她将测试是否会提早 暴露于非保护性机械通风与脑损伤后ARDS相关(目标3)。解决这个问题 知识差距可能导致干预措施，以预防ARDS并改善该患者的预后 人口。本建议书中概述的研究和培训将构成R01级建议书的基础 旨在研究预防和治疗创伤后ARDS的干预措施。

PROJECT SUMMARY/ ABSTRACT This is an application for a K23 award for Dr. Carolyn Hendrickson, a pulmonary and critical care physician at the University of California, San Francisco. Dr. Hendrickson is establishing herself as a young investigator in patient-oriented research of acute respiratory distress syndrome (ARDS), with a focus on the biologic mechanisms of ARDS after traumatic brain injury (TBI). This K23 award will provide Dr. Hendrickson with the support necessary to accomplish the following goals: (1) to become an expert clinical and translational researcher in ARDS after traumatic injury; (2) to study the biologic mechanisms of ARDS after TBI involving platelet biology, endothelial activation, and lung injury induced by mechanical ventilation; (3) to implement advanced analyses of complex observational data, including machine learning; (4) to develop an independent translational research career. Dr. Hendrickson's plan to achieve these goals is supported by a multidisciplinary mentoring team of experts. Her primary mentor, Dr. Michael Matthay, has extensive experience in translational ARDS research and in the career development of early stage investigators. Dr. Hendrickson will work with four co-mentors: Dr. Mitchell Cohen, a translational researcher studying coagulation after trauma, Dr. Alan Hubbard, a biostatistician specializing in causal inference, Dr. Geoffrey Manley, a neurosurgeon and leading investigator in TBI research, and Dr. Mark Looney, an expert platelet biology and lung injury. The development of ARDS after TBI is common and is associated with worse neurological outcomes. The biologic mechanisms driving ARDS after TBI are poorly understood. The central hypothesis of this proposal is that the risk of ARDS after TBI is mediated through activated vascular endothelium and platelets as well as non-protective mechanical ventilation strategies that use large tidal volumes. Dr. Hendrickson will investigate these causal pathways utilizing previously collected data and plasma from an ongoing observational cohort study. In this same cohort she will prospectively collect biospecimens, detailed mechanical ventilation data, and lung ultrasound images. This proposal represents an innovative approach to studying ARDS after TBI using carefully adjudicated exposures and outcomes. Dr. Hendrickson will test whether plasma biomarkers of endothelial activation, vascular permeability, and inflammation (Aim 1) and platelet function, activation, and aggregation (Aim 2) are associated with ARDS after TBI. She will collect lung ultrasound images and frequent mechanical ventilation data including tidal volumes and plateau pressures. She will test whether early exposure to non-protective mechanical ventilation is associated with ARDS after TBI (Aim 3). Addressing this gap in knowledge may lead to interventions that prevent ARDS and improve outcomes in this patient population. The research and training outlined in this proposal will form the basis for an R01-level proposal designed to study interventions to prevent and treat ARDS after traumatic injury.