Cerebrovascular Dysfunction in Newborns with HIE during Hypothermia and Rewarming

描述(由申请者提供)：这份以患者为导向的研究职业发展奖(K23)申请书概述了候选人未来作为一名NIH资助的新生儿缺氧缺血性脑病(HIE)独立临床研究员的科学生涯的3年计划。出生窒息是数百万婴儿的主要全球公共卫生负担。低温仍然是唯一可用的神经保护疗法，但多达一半的接受治疗的婴儿结局不佳。关于损伤的严重程度和治疗反应的血管机制，存在着巨大的知识差距。了解HIE中神经血管单位的控制和调节以及低温对其的影响是一个新的基本概念，构成了候选人研究计划和职业发展的重点。该研究项目的首要目标是评估轻度、中度和重度HIE的脑血管功能，以确定脑血管功能的变化如何反映MRI检测到的脑损伤程度和癫痫的发生。在接受低温治疗的中到重度HIE的新生儿中，将进一步检查功能失调的自动调节，以测试在更深/更长的低温方案和复温过程中它是如何调节的。最终，候选人将确定脑血管功能评估是否可以作为HIE婴儿损伤严重程度的可靠生物标记物和低温治疗后预后的相关性。为了实现这一目标，将使用最先进的无创近红外光谱(NIRS)和经颅多普勒测量出生后5天的脑自我调节和脑组织氧合；在出生后10-14天将进行MRI检查，以评估新生儿HIE脑损伤的严重程度。在他们的学术研究领域，一个由多学科领导人组成的经验丰富的指导团队将确保候选人成功过渡到独立。她的具体职业发展目标是：1)发展脑血管自动调节和神经生理学方面的新专业知识，2)学习高级频谱统计分析、多中心临床方案开发和领导技能。第一个GAL是利用和解释新的脑自动调节监测技术，以揭示损伤的机制和治疗反应的关键。第二个目标是保持专注，获得可交付成果，并通过在RO1融资方面变得具有竞争力而走向独立。在了解脑血管反应作为脑损伤严重程度的生物标志物以及神经保护疗法对其调节方面的专业知识，以及领导能力和临床试验的进行，将使应聘者成为一名独立的临床研究员。这些知识将是获得R01资金的关键，因为它是评估新的神经保护方式的必要基础，以优化HIE后的神经发育结果。

DESCRIPTION (provided by applicant): This Mentored Patient-Oriented Research Career Development Award (K23) application outlines the candidate's 3-year plan to establish her future scientific career as an independent NIH-funded clinical investigator in neonatal hypoxic-ischemic encephalopathy (HIE). Birth asphyxia constitutes a major global public health burden for millions of infants. Hypothermia remains the sole neuroprotective therapy available, yet as many as half of treated infants have poor outcomes. There is a huge knowledge gap relative to vascular mechanisms underlying the severity of injury and responses to therapy. Understanding the control and modulation of the neurovascular unit in HIE and how it is affected by hypothermia is a novel and fundamental concept that forms the focus of both the candidate's research plan and career development. The overarching goal of the research project is to assess cerebrovascular function in a spectrum of mild, moderate and severe HIE to determine how changes in cerebrovascular function reflect the extent of cerebral injury as detected by MRI and occurrence of seizures. Dysfunctional autoregulation will be further examined in newborns with moderate to severe HIE undergoing hypothermia therapy to test how it is modulated with a deeper/longer hypothermia regimen and during the rewarming process. Ultimately, the candidate will determine if assessment of cerebrovascular function can be used as a reliable biomarker of injury severity and a correlate of outcome following hypothermia therapy in HIE infants. To achieve this goal, state-of-the-art noninvasive near infrared spectroscopy (NIRS) and transcranial Doppler will be used to measure cerebral autoregulation and cerebral tissue oxygenation for the first 5 days of age; MRI will be done at 10-14 days to evaluate severity of brain injury in newborns with HIE. An experienced multidisciplinary mentoring team of leaders in their field of academic research will ensure the candidate's successful transition to independence. Her specific career development objectives are: 1) to develop new expertise in cerebrovascular autoregulation and neurophysiology, and 2) to learn advanced spectral statistical analysis, multicenter clinical protocol development, and leadership skills. The first gal is pivotal for utilizing and interpreting new cerebral autoregulation monitoring technology in orde to unravel the mechanisms of injury and responses to therapy. The second goal is essential to remain focused, acquire deliverables and move to independence by becoming competitive for RO1 funding. Building expertise in understanding cerebrovascular responses as biomarkers of severity of brain injury as well as their modulation with neuroprotective therapy, along with competence in leadership and the conduct of clinical trials, will allow the candidate to become an independent clinical investigator. This knowledge will be crucial for the procurement of R01 funding by serving as a necessary groundwork for assessment of new neuroprotective modalities to optimize neurodevelopmental outcomes following HIE.