Validating MRS lipids as biomarkers of brain injury in neonates with hypoxic-ischemic encephalopathy

验证 MRS 脂质作为缺氧缺血性脑病新生儿脑损伤的生物标志物

• 批准号: 10178067
• 负责人: Jessica L Wisnowski
• 金额: $ 13.85万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178067
• 关键词: Address; Adjuvant; Adjuvant Therapy; Age; Age-Months; Animal Model; Asphyxia; Attenuated; Bioinformatics; Biological Markers; Biophysics; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cause of Death; Cell Death; Cell membrane; Cellular biology; Cerebrum; Cessation of life; Clinical; Clinical Management; Clinical Research; Clinical Trials; Complex; Computing Methodologies; Coupling; Data; Death Rate; Development; Development Plans; Diagnosis; Doctor of Philosophy; Dose; Educational workshop; Encephalopathies; Ensure; Erythropoietin; Functional disorder; Funding; Future; Goals; Gold; Histologic; Hyperbilirubinemia; Image; Infant; Injury; Interruption; Journals; K-Series Research Career Programs; Knowledge; Laboratory Research; Lipids; Macaca; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Membrane Lipids; Mentors; Mentorship; Methods; Modeling; Molecular; Multi-Institutional Clinical Trial; Neurodevelopmental Impairment; Outcome; Parents; Participant; Perinatal Brain Injury; Pharmacologic Substance; Phase; Phase I/II Trial; Physics; Physiological; Placebos; Premature Birth; Process; Randomized; Randomized Controlled Trials; Research; Research Methodology; Research Personnel; Research Project Grants; Resources; Scientist; Secure; Sensitivity and Specificity; Severities; Standardization; Stroke; Surrogate Endpoint; Term Birth; Testing; Therapeutic; Training; United States National Institutes of Health; Work; adverse outcome; behavioral outcome; career development; clinical translation; computer program; design; early detection biomarkers; improved; indexing; infant death; meetings; mortality risk; natural hypothermia; neonatal hypoxic-ischemic brain injury; neonate; nervous system disorder; neuroimaging marker; neuroprotection; novel; patient population; perinatal complications; phase 3 study; potential biomarker; pre-clinical; preclinical study; preclinical trial; predictive marker; primary endpoint; repaired; response to brain injury; secondary analysis; secondary endpoint; skills; standard of care; success; treatment duration; treatment response; virtual

ABSTRACT Jessica L. Wisnowski, PhD is a clinical scientist focused on the development and application of novel neuroimaging biomarkers to aid in the diagnosis of perinatal brain injury and the management of neuroprotective therapies. This mentored career development award will provide her with advanced training and skills in magnetic resonance imaging (MRI), bioinformatics, and cell biology, all of which are essential to ensure her success as an independent investigator leading a clinical translational imaging research laboratory. RESEARCH CONTEXT: Establishing safe and effective neuroprotective therapies for neonatal hypoxic- ischemic encephalopathy (HIE) and other neurological diseases is a priority for the NIH. More than a dozen pharmaceutical agents have shown efficacy for neuroprotection in preclinical trials. To facilitate clinical translation, there is a pressing need for well-validated biomarkers that can accurately document the severity of brain injury, response to neuroprotective therapies, and predict long-term neurodevelopmental outcomes in neonates with HIE. This K23 career development proposal leverages data from the ongoing High-dose Erythropoietin (Epo) for Asphyxia and Encephalopathy (HEAL) trial (NCT02811263) to develop robust, quantitative neuroimaging biomarkers of brain injury for neonatal HIE. The parent HEAL trial, a phase III, randomized-controlled trial, seeks to determine if the combination of Epo + hypothermia (HT) reduces the combined rate of death and neurodevelopmental impairment at 22-26 months over HT alone. Using data from the HEAL Trial, this K23 research project will determine whether lipids, measured non-invasively by MR Spectroscopy (MRS), provide a valid estimate of injury severity and treatment response in neonates with HIE. Under normal physiological conditions, CNS lipids are membrane-bound and highly organized, rendering them virtually undetectable by MRS due to their limited mobility and strong dipolar coupling. However, after hypoxia- ischemia, MRS lipids rise. Prior research has established an association between the rise in MRS lipids and histological indices of brain injury. This project will determine whether MRS lipids are valid predictors of death and neurodevelopmental impairment. As proof of principle that MRS lipids can be used as surrogate endpoints in multisite clinical trials, this study will determine whether Epo therapy decreases the severity of brain injury as evidenced by the MRS lipid biomarkers. CAREER DEVELOPMENT PLAN: Dr. Wisnowski will complete coursework in MR physics, advanced MRS methods, computer programming, bioinformatics and computational methods and then will apply this knowledge and skillset directly to execute her proposed research methods. Dr. Wisnowski’s career development goals will be supported through close mentorship from an interdisciplinary team, attendance at professional meetings and workshops, and participation in seminars and journal clubs, as she works toward securing independent funding.

摘要 杰西卡湖Wisnowski博士是一位临床科学家，专注于开发和应用新型 神经影像学生物标志物，以帮助诊断围产期脑损伤和管理 神经保护疗法这个指导职业发展奖将为她提供高级培训 以及磁共振成像（MRI）、生物信息学和细胞生物学方面的技能，所有这些对于 确保她作为一个独立的研究者领导临床转化成像研究实验室的成功。 研究背景：为新生儿缺氧建立安全有效的神经保护疗法- 缺血性脑病（HIE）和其他神经系统疾病是NIH的优先事项。十多 药物制剂在临床前试验中显示出神经保护的功效。为了便于临床 翻译，迫切需要经过充分验证的生物标志物，可以准确地记录严重性， 脑损伤，对神经保护治疗的反应，并预测长期的神经发育结果， 新生儿HIE。这份K23职业发展提案利用了正在进行的高剂量 促红细胞生成素（Epo）治疗窒息和脑病（HEAL）试验（NCT 02811263）， 新生儿缺氧缺血性脑病脑损伤的定量神经影像学生物标志物母公司HEAL试验，第三阶段， 一项随机对照试验，旨在确定Epo +低温（HT）联合治疗是否能减少 与单独HT相比，22-26个月时死亡和神经发育障碍的综合发生率。使用的数据来自 HEAL试验，这个K23研究项目将确定是否脂质，测量非侵入性的MR 波谱（MRS），提供了一个有效的估计损伤的严重程度和治疗反应的新生儿缺氧缺血性脑病。 在正常生理条件下，CNS脂质是膜结合的，并且高度组织化，使得它们 由于其有限的迁移率和强偶极耦合，实际上无法被MRS检测到。但是缺氧后- 缺血，MRS脂质升高。先前的研究已经建立了MRS脂质升高与 脑损伤的组织学指标。该项目将确定MRS脂质是否是死亡的有效预测因子 和神经发育障碍。作为MRS脂质可用作替代终点的原理证明 在多中心临床试验中，这项研究将确定Epo治疗是否能降低脑损伤的严重程度， 由MRS脂质生物标志物证实。职业发展简介：Wisnowski博士将完成 课程在MR物理学，先进的MRS方法，计算机编程，生物信息学和 计算方法，然后将这些知识和技能直接应用于执行她提出的 研究方法Wisnowski博士的职业发展目标将通过以下方面的密切指导得到支持： 一个跨学科的团队，出席专业会议和讲习班，并参加研讨会 和期刊俱乐部，因为她努力争取独立的资金。