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

项目概要/摘要 这是一份K23奖的申请书，申请人是卡罗琳·亨德里克森博士，她是一名肺科和重症监护医生， 加州大学旧金山分校弗朗西斯科。亨德里克森博士正在建立自己作为一个年轻的调查员， 急性呼吸窘迫综合征（ARDS）的患者导向研究，重点是生物 创伤性脑损伤（TBI）后ARDS的机制。K23奖将为Hendrickson博士提供 为实现以下目标提供必要的支持：（1）成为临床和翻译专家 目的：（1）探讨创伤性脑损伤后ARDS的生物学机制， 血小板生物学、内皮活化和机械通气引起的肺损伤;（3）实施 复杂观测数据的高级分析，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多学科的支持。 指导专家团队。她的主要导师Michael Matthay博士在翻译领域拥有丰富的经验， ARDS研究和早期研究人员的职业发展。亨德里克森博士将与四名 共同导师：米切尔科恩博士，创伤后凝血研究的翻译研究员，艾伦博士 哈伯德，一个生物统计学家专门从事因果推理，杰弗里曼利博士，神经外科医生和领导 TBI研究的调查员，以及血小板生物学和肺损伤专家Mark Looney博士。 创伤性脑损伤后发生急性呼吸窘迫综合征是常见的，并且与更差的神经功能结局相关。的 TBI后驱动ARDS的生物学机制知之甚少。这一提议的核心假设是 TBI后ARDS的风险是通过活化的血管内皮和血小板介导的， 使用大潮气量的非保护性机械通气策略。亨德里克森医生会调查 这些因果途径利用先前收集的数据和来自正在进行的观察队列的血浆 study.在同一队列中，她将前瞻性收集生物标本、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创新的方法来研究创伤性脑损伤后的ARDS 使用仔细裁定的暴露和结果。亨德里克森博士将测试是否血浆生物标志物 内皮活化、血管通透性和炎症（目标1）以及血小板功能、活化和 聚集（Aim 2）与TBI后的ARDS相关。她将收集肺部超声图像， 机械通气数据，包括潮气量和平台压力。她将测试是否早 暴露于非保护性机械通气与TBI后的ARDS相关（目的3）。解决这一 知识的差距可能导致干预措施，预防ARDS和改善结果，在这个病人 人口本提案中概述的研究和培训将构成R 01级提案的基础 旨在研究预防和治疗创伤性损伤后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.