DIASTOLIC CLOSING MARGIN PREDICTS BRAIN INJURY IN PREMATURE INFANTS

 描述(由申请人提供)：这是贝勒医学院(BCM)和德克萨斯儿童医院(TCH)儿科助理教授兼董事会认证新生儿专家Christopher Rhee博士的K23奖修订申请。我很有资格，也很有动力从事学术医学的事业，重点研究新生儿脑损伤和脑血流动力学。这个K23奖项将为我提供必要的支持，以：(1)成为早产儿脑损伤的专家；(2)进行临床研究，以确定最佳的脑血流灌注参数；(3)将脑血流灌注的变化与脑室间出血(IVH)、白质损伤和神经发育结局联系起来；(4)收集数据，以设计干预试验，根据个性化的脑血流灌注参数识别和治疗患者；以及(5)发展独立的研究事业。我将利用德克萨斯医学中心的研究和教育资源来推进我的研究事业发展。TCH的新生儿重症监护病房是全国最大的新生儿重症监护室之一，提供了向特别多的早产儿学习的机会和资源。每年有100多名出生体重为1000克的早产儿在TCH出生，我们有多样性和数量的患者来进行有意义的临床研究并对患者护理产生影响。我已经组建了一个知识渊博的、多样化的、多学科的指导小组，来自新生儿科、重症监护科、麻醉学、神经病学、神经放射学和发育儿科学，以指导我的职业生涯和这项提议。在过去的5年里，我一直在Ken Brady，M.D.(二级导师)的基础科学实验室工作，学习失血性休克动物模型中脑和肾脏灌注监测的技术，并将这些应用程序翻译到早产儿身上。我已经发表了动物和临床研究的结果。在过去的三年里，我一直与首席导师Jeffrey R.Kaiser医学博士合作，进一步了解早产儿脑血流动力学的发展，探索使用磁共振成像技术评估脑白质损伤，并学习经颅多普勒超声技术临床评估早产儿脑血流的技术。与研究计划相结合，我打算发展技能集，成为早产儿脑损伤的领导者。为了实现这些目标，我将利用我的导师和咨询委员会的资源和专业知识。我将正式参加授课课程，进行精选阅读，并参加关于大脑生理学和神经成像的研讨会，以拓宽我的知识基础。此外，我还将从Kaiser博士那里学习经颅多普勒，从Brady博士那里学习高级生理波形分析，从伊丽莎白·王尔德博士和Jill Hunter博士那里学习神经成像技术。最后，我将每周与我的主要和次要导师会面，每季度与我的咨询委员会会面，评估我的进步，讨论我职业发展计划的变化。我现在已经开发出一个大脑灌注参数，舒张期关闭边缘(DCM)，它提供了一种新的方法，将动脉血压正常化到脑血管系统的临界关闭压(零流压)。我的初步发现表明高脑灌注压(高DCM)与IVH有关，我已经在2014年儿科学术学会会议上口头介绍了这一数据，并发表了这项工作的两篇手稿。Kaiser博士和Brady博士将为我提供研究工具、研究空间和科学指导，帮助确保我的成功。这项建议的目的是评估DCM预测早产儿出血性和缺血性脑损伤的能力。我的中心假设是，高DCM与IVH相关，表明高灌注性损伤，而低DCM与脑白质损伤相关，表明缺血性损伤。如果这一假设是正确的，那么早产儿最常见的脑损伤的机制和逻辑护理目标将被描绘出来。我的长期目标是确定临床上相关的脑血流动力学参数，这些参数可以在床边使用，以防止出血性和缺血性脑损伤，从而改善神经发育结果。我将收集必要的初步数据，以设计未来的血流动力学干预试验，旨在预防最常见的形式的过早脑损伤，在随后的R01：目的1。前瞻性地确定高脑灌流压(高DCM)是否预示脑室间出血。目的2.前瞻性地确定低脑灌注压(低DCM)是否预示脑白质损伤。目的3.确定脑血流灌注的生理测量是否可以预测神经发育结果。K23将让我有足够的时间进行这项研究，并继续我的职业发展，朝着成为一名成功和独立的临床科学家的目标前进。

 DESCRIPTION (provided by applicant): This is a revised application for a K23 Award for Dr. Christopher Rhee, an assistant professor and board- certified neonatologist in the Department of Pediatrics at Baylor College of Medicine (BCM) and Texas Children's Hospital (TCH). I am well-qualified and highly motivated to pursue a career in academic medicine with a research focus on neonatal brain injury and cerebral hemodynamics. This K23 award will provide the support necessary for me to: (1) become an expert in premature brain injury; (2) conduct clinical investigations to define optimal brain perfusion parameters; (3) relate changes in brain perfusion to outcomes of interventricular hemorrhage (IVH), white matter injury, and neurodevelopmental outcomes; (4) gather data for the purpose of designing an intervention trial to identify and treat patients based on individualized brain perfusion parameters; and (5) develop an independent research career. I will use research and educational resources at the Texas Medical Center to advance my research career development. The neonatal intensive care unit at TCH is one of the largest in the country and offers the opportunity and resources to learn from an especially large population of premature infants. With more than 100 premature infants with birth weight ≤1000 grams born at TCH annually, we have the diversity and number of patients to perform meaningful clinical research and make an impact on patient care. I have assembled a knowledgeable, diverse, and multidisciplinary mentoring group from neonatology, critical care, anesthesiology, neurology, neuroradiology and developmental pediatrics to guide my career and this proposal. I have been working for the past 5 years in the basic science laboratory of Ken Brady, M.D., (secondary mentor) to learn techniques of brain and kidney perfusion monitoring in animal-models of hemorrhagic-induced shock and have translated these applications to premature infants. I have published the results of both animal and clinical research. Over the past 3 years, I have been working with Jeffrey R. Kaiser, M.D., (primary mentor) to further understand the development of premature cerebral hemodynamics, to explore use of magnetic resonance imaging techniques to evaluate white matter brain injury, and to learn the technique of transcranial Doppler ultrasound to evaluate cerebral blood flow clinically in premature infants. In conjunction with the research plan, I intend develop the skill set to become a leader in premature brain injury. To achieve these goals, I will utilize the resources and expertise of my mentors and Advisory Committee. I will formally take didactic courses, perform selected readings, and attend symposiums on brain physiology and neuroimaging to broaden my knowledge base. In addition, I will have hands-on tutorials learning transcranial Doppler from Dr. Kaiser, advanced physiologic waveform analysis from Dr. Brady, and neuroimaging techniques from Drs. Elisabeth Wilde, Ph.D. and Jill Hunter, Ph.D. Finally, I will meet weekly with my primary and secondary mentor and quarterly with my Advisory Committee to evaluate my progress and discuss changes to my career development plan. I have now developed a brain perfusion parameter, the diastolic closing margin (DCM) that offers a novel way to normalize arterial blood pressure to the critical closing pressure (zero-flow pressure) of the brain vasculature. My preliminary findings demonstrate an association of high brain perfusion pressure (high DCM) with IVH, and I have orally presented this data at the 2014 Pediatric Academic Society meeting and have published two manuscripts from this work. Drs. Kaiser and Brady will provide me with the research tools, research space and scientific guidance to help to ensure my success. The objective of this proposal is to assess the ability of the DCM to predict hemorrhagic and ischemic brain injury in premature infants. My central hypothesis is that a high DCM is associated with IVH, indicating a hyperperfusion injury, and a low DCM is associated with white matter injury, indicating an ischemic injury. If this hypothesis is correct, the mechanism and logical care goals for the most common brain injuries in premature infants will be delineated. My long-term goal is to define clinically relevant brain-specific hemodynamic parameters that can be used at the bedside to prevent hemorrhagic and ischemic brain injury and thereby improve neurodevelopmental outcomes. I will gather necessary preliminary data for the design of a future hemodynamic intervention trial aimed at preventing the most common forms of premature brain injury, in a subsequent R01: Aim 1. Prospectively determine whether a high brain perfusion pressure (high DCM) is predictive of interventricular hemorrhage. Aim 2. Prospectively determine whether a low brain perfusion pressure (low DCM) is predictive of white matter injury. Aim 3. Determine whether physiologic measurements of brain perfusion are predictive of neurodevelopmental outcomes. The K23 will allow me the protected time to conduct this research and continue my career development towards my goal of becoming a successful and independent clinical scientist.