Cerebrovascular Dysfunction in Newborns with HIE during Hypothermia and Rewarming

描述（由申请人提供）：这份指导患者导向研究职业发展奖（K23）申请概述了候选人作为美国国立卫生研究院资助的新生儿缺氧缺血性脑病（HIE）独立临床研究者的3年计划，以建立她未来的科学事业。出生窒息是全球数百万婴儿的主要公共卫生负担。低温治疗仍然是唯一可用的神经保护疗法，然而多达一半的接受治疗的婴儿预后不佳。在损伤严重程度和治疗反应的血管机制方面存在巨大的知识差距。了解HIE中神经血管单元的控制和调节以及它如何受到低温的影响是一个新颖而基本的概念，是候选人研究计划和职业发展的重点。该研究项目的总体目标是评估轻度、中度和重度HIE患者的脑血管功能，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发作的发生。在接受低温治疗的中度至重度HIE新生儿中，将进一步检查功能失调的自我调节，以测试如何通过更深/更长时间的低温治疗方案和在重新升温过程中进行调节。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志物和低温治疗后结果的相关性。为了实现这一目标，最先进的无创近红外光谱（NIRS）和经颅多普勒将用于测量出生后5天的大脑自动调节和脑组织氧合；MRI将在10-14天进行评估新生儿HIE脑损伤的严重程度。一个由学术研究领域的领导者组成的经验丰富的多学科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)在脑血管自动调节和神经生理学方面发展新的专业知识；2)学习先进的光谱统计分析，多中心临床方案制定和领导技能。第一个gal是利用和解释新的大脑自动调节监测技术以揭示损伤和治疗反应机制的关键。第二个目标是保持专注，获得可交付成果，并通过竞争RO1资金而走向独立。在理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治疗对其的调节方面建立专业知识，以及领导能力和临床试验的实施，将使候选人成为一名独立的临床研究者。这些知识对于获得R01资金至关重要，可以作为评估新的神经保护模式以优化HIE后神经发育结果的必要基础。

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.