Cerebrovascular Dysfunction in Newborns with HIE during Hypothermia and Rewarming

新生儿 HIE 低温和复温期间的脑血管功能障碍

• 批准号: 8696939
• 负责人: LINA F CHALAK
• 金额: $ 12.33万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696939
• 关键词: Address; Affect; Age; Age-Months; Asphyxia; Biological Markers; Birth; Blood Vessels; Brain; Brain Injuries; Cause of Death; Cerebral Palsy; Cerebrum; Chronic Disease; Clinical; Clinical Investigator; Clinical Protocols; Competence; Complement; Conduct Clinical Trials; Development; Electroencephalography; Ensure; Functional disorder; Funding; Future; Goals; Health; Healthy People 2010; Homeostasis; Hour; Impairment; Infant; Injury; Ischemic Brain Injury; Knowledge; Leadership; Learning; Life; Magnetic Resonance Imaging; Measurement; Measures; Mental Retardation; Mentored Patient-Oriented Research Career Development Award; Mentors; Metabolic; Mission; Modality; Monitor; National Institute of Child Health and Human Development; Near-Infrared Spectroscopy; Neonatal; Neonatal Brain Injury; Neurodevelopmental Impairment; Newborn Infant; Outcome; Phase; Process; Public Health; Quality of life; Randomized; Regimen; Relative (related person); Research; Research Project Grants; Rewarming; Role; Secondary to; Seizures; Severities; Societies; Subgroup; Technology; Testing; United States National Institutes of Health; brain tissue; career; career development; cerebrovascular; design; experience; functional outcomes; hemodynamics; improved; interest; multidisciplinary; natural hypothermia; neonatal hypoxic-ischemic brain injury; neurodevelopment; neurophysiology; neuroprotection; neurovascular unit; novel; novel strategies; predictive modeling; protocol development; response; response to injury; skills; success; tissue oxygenation

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.

描述（由申请人提供）：这个指导以患者为导向的研究职业发展奖（K23）应用程序概述了候选人的3年计划，以建立她未来的科学生涯作为一个独立的NIH资助的临床研究新生儿缺氧缺血性脑病（HIE）。出生窒息是数百万婴儿的一个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，但多达一半的治疗婴儿的结果不佳。关于损伤严重程度和治疗反应的血管机制存在巨大的知识缺口。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，形成了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。将在接受低温治疗的中度至重度HIE新生儿中进一步检查功能失调的自动调节，以测试其如何通过更深/更长的低温方案和复温过程进行调节。最终，候选人将确定脑血管功能的评估是否可用作损伤严重程度的可靠生物标志物以及缺氧缺血性脑病婴儿低温治疗后结果的相关因素。为了实现这一目标，将使用最先进的无创近红外光谱（NIRS）和经颅多普勒测量前5天的脑自动调节和脑组织氧合;将在10-14天进行MRI，以评估HIE新生儿脑损伤的严重程度。 一个经验丰富的多学科指导团队的领导者在他们的学术研究领域将确保候选人的成功过渡到独立。她具体的职业发展目标是：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）学习高级光谱统计分析，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的关键，以揭示损伤和治疗反应的机制。第二个目标是保持重点，获得可交付成果，并通过竞争获得RO 1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其与神经保护治疗的调节方面建立专业知识，沿着领导能力和临床试验的开展，将使候选人成为独立的临床研究者。这些知识将是至关重要的采购R 01资金作为一个必要的基础，评估新的神经保护模式，以优化神经发育的结果后HIE。

项目成果

Obstetric antecedents to body-cooling treatment of the newborn infant.

新生儿身体冷却治疗的产科前因。

• DOI: 10.1016/j.ajog.2014.02.013
• 发表时间: 2014
• 期刊: American journal of obstetrics and gynecology
• 影响因子: 9.8
• 作者: Nelson,DavidB;Lucke,AshleyM;McIntire,DonaldD;Sánchez,PabloJ;Leveno,KennethJ;Chalak,LinaF
• 通讯作者: Chalak,LinaF

Placental clearance/synthesis of neurobiomarkers GFAP and UCH-L1 in healthy term neonates and those with moderate-severe neonatal encephalopathy.

健康足月新生儿和患有中重度新生儿脑病的神经生物标志物 GFAP 和 UCH-L1 的胎盘清除/合成。

• DOI: 10.1038/s41390-019-0439-z
• 发表时间: 2019
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Mir,ImranN;StevenBrown,L;Rosenfeld,CharlesR;Chalak,LinaF
• 通讯作者: Chalak,LinaF

The "neurovascular unit approach" to evaluate mechanisms of dysfunctional autoregulation in asphyxiated newborns in the era of hypothermia therapy.

• DOI: 10.1016/j.earlhumdev.2014.06.013
• 发表时间: 2014-10
• 期刊: EARLY HUMAN DEVELOPMENT
• 影响因子: 2.5
• 作者: Chalak, Lina F.;Tarumi, Takashi;Zhang, Rong
• 通讯作者: Zhang, Rong

Introduction. A "neurovascular unit" approach in newborns with HIE: can we improve outcomes?

介绍。

• DOI: 10.1016/j.earlhumdev.2014.06.011
• 发表时间: 2014
• 期刊: Early human development
• 影响因子: 2.5
• 作者: Chalak,LinaF

Predictive value of neonatal MRI showing no or minor degrees of brain injury after hypothermia.

• DOI: 10.1016/j.pediatrneurol.2014.01.013
• 发表时间: 2014-05
• 期刊: PEDIATRIC NEUROLOGY
• 影响因子: 3.8
• 作者: Rollins, Nancy;Booth, Timothy;Morriss, Michael C.;Sanchez, Pablo;Heyne, Roy;Chalak, Lina
• 通讯作者: Chalak, Lina