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

摘要 杰西卡·L·威斯诺斯基博士是一位临床科学家，专注于新型药物的开发和应用 神经影像生物标志物在围产期脑损伤诊断和治疗中的应用 神经保护性疗法。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，所有这些都是 确保她作为领导临床转化成像研究实验室的独立调查员取得成功。 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)和其他神经疾病是NIH的优先事项。十几个 在临床前试验中，药物已显示出对神经保护的有效性。以方便临床 翻译，迫切需要经过良好验证的生物标记物，能够准确地记录 脑损伤、对神经保护治疗的反应和预测长期神经发育结果 新生儿缺氧缺血性脑病。这份K23职业发展计划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(HEAR)试验(NCT02811263)开发强大的， 新生儿缺氧缺血性脑病脑损伤的定量神经影像生物标志物。父母治愈试验，第三阶段， 一项随机对照试验，旨在确定EPO亚低温(HT)联合应用是否能降低 单纯高血压患者22-26个月的死亡率和神经发育障碍的综合发生率。使用来自 这项K23研究项目将确定由MR非侵入性测量的血脂 波谱(MRS)为新生儿缺氧缺血性脑病的损伤严重程度和治疗反应提供了有效的估计。 在正常生理条件下，中枢神经系统脂类是膜结合的，高度组织化，使它们 由于其有限的迁移率和强烈的偶极耦合，实际上无法被MRS检测到。然而，在缺氧之后- 脑缺血时，夫人血脂升高。先前的研究已经确定了MRS血脂的增加和 脑损伤的组织学指标。该项目将确定脂肪夫人是否为有效的死亡预测指标。 和神经发育障碍。作为MRS Lipid可用作替代终点的原则的证据 在多点临床试验中，这项研究将确定EPO治疗是否降低了脑损伤的严重程度 MRS脂质生物标记物证明了这一点。职业发展计划：威斯诺斯基博士将完成 MR物理学、高级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来自 跨学科团队，参加专业会议和研讨会，并参加研讨会 和杂志俱乐部，因为她致力于获得独立的资金。

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.