Precision Therapy for Neonatal Brain Injury

新生儿脑损伤的精准治疗

• 批准号: 9160837
• 负责人: Donna M. Ferriero
• 金额: $ 65.27万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9160837
• 关键词: Biochemical; Biological Assay; Brain; Brain Injuries; CRISPR/Cas technology; Carbon; Cause of Death; Cell Compartmentation; Cerebral Palsy; Cerebrum; ChIP-seq; Child; Clinic; Clinical Research; Epilepsy; Evolution; Genetic; Human; Hypoxia Inducible Factor; Imaging Techniques; In Vitro; Individual; Inflammation; Injury; Link; Magnetic Resonance Spectroscopy; Mental Retardation; Metabolic; Molecular; Mus; Neonatal Brain Injury; Newborn Infant; Oxygen; Pathway interactions; Patients; Phase; Precision therapeutics; Protons; Recovery; Regulation; Signal Pathway; Signal Transduction; Spectrum Analysis; Techniques; Therapeutic; Time; Translating; disability; excitotoxicity; improved outcome; in vivo; individualized medicine; innovation; metabolic imaging; molecular targeted therapies; natural hypothermia; neonatal hypoxic-ischemic brain injury; neurovascular; novel; oxidant stress; postnatal; public health relevance; repaired; responders and non-responders; response; response to injury; standard of care; therapy design; tool

Project Summary/Abstract Section Neonatal brain injury is an important cause of death and disability, with pathways of oxidant stress, inflammation, and excitotoxicity leading to damage that progress over a long period of time. Therapies have classically targeted individual pathways during early phases of injury, but targeting pathways later in the injury response may be additionally effective. Therapeutic hypothermia (TH), while being standard of care for hypoxic-ischemic encephalopathy (HIE), provides protection only in 60% of babies. The overarching hypothesis is that the metabolic state of the brain immediately after TH differs markedly between hypothermia responders and non-responders. We will identify the metabolic state after TH using proton and hyperpolarized carbon 13 spectroscopy and then study cellular pathways to identify more precise and individualized treatment approaches. We will use postnatal day 9 mice and follow them through injury evolution. The studies outlined in this proposal reflect an innovative and systematic approach to the study of HI brain injury in the newborn because they combine advanced metabolic imaging techniques (proton and carbon spectroscopy) and cell-signaling studies, focusing on HIF signaling, that will both inform and be informed by human clinical studies. Utilizing genetic cellular approaches in which components of the injury response are specifically deleted/disrupted in the specific cell compartments will allow us to evaluate the benefits of the neurovascular niche in vivo. We will broadly interrogate HIF-dependent signaling pathways following injury using ChIP-Seq. Together, these genetic tools will allow us to explore the molecular regulation of HI both in vitro and in vivo to better identify more appropriate molecular targets for therapy for the individual needing them the most. By investigating responses to HI at a cellular level using traditional biochemical assays and global level in the brain using MR spectroscopy, we aim to make a link between specific cellular changes and metabolic changes that can be detected non-invasively. This approach would eventually allow the findings to be translated into the clinic and potentially change the management of patients. We will use in vitro techniques such as CRISPr/Cas9 and Chip-seq to dissect important signaling pathways like hypoxia inducible factor (HIF). We will also use an invitro approach when we identify appropriate targets and design therapies to counteract deficient repair. Thus, defining the cerebral metabolic signature of non- responders will identify subsequent novel pathways to target, and will lead to improved outcomes that could never be achieved by only targeting pathways through hypothermia alone. Understanding how the cascade of injury responses occur and the key modulators during each phase will lead to more rationale therapies.

项目概要/摘要部分 新生儿脑损伤是死亡和残疾的重要原因，其途径是氧化应激， 炎症和兴奋性毒性导致损害，其在很长一段时间内进展。疗法 在损伤的早期阶段经典地靶向单个通路，但在损伤的后期靶向通路。 损伤反应可能是额外有效。治疗性低温（TH），同时作为标准护理 对于缺氧缺血性脑病（HIE），仅对60%的婴儿提供保护。总体 假设是，TH后大脑的代谢状态在以下两种情况下明显不同： 低体温反应者和无反应者。我们将确定TH后的代谢状态使用质子和 超极化碳13光谱，然后研究细胞途径，以确定更精确， 个性化的治疗方法。我们将使用出生后第9天的小鼠， 进化本提案中概述的研究反映了对研究 HI脑损伤的新生儿，因为他们联合收割机先进的代谢成像技术（质子和 碳光谱）和细胞信号传导研究，重点是HIF信号传导，这将为我们提供信息， 通过人类临床研究得知。利用遗传细胞方法，其中损伤的组成部分 在特定细胞区室中特异性缺失/破坏的反应将使我们能够评估 体内神经血管生态位的益处。我们将广泛地研究HIF依赖的信号通路 使用ChIP-Seq.这些基因工具将使我们能够探索 在体外和体内调节HI以更好地鉴定用于治疗的更合适的分子靶标， 最需要它们的人通过在细胞水平上研究HI的反应，使用传统的 我们的目标是利用磁共振波谱学在大脑中进行生化测定和全球水平的联系， 特定的细胞变化和代谢变化，可以非侵入性地检测。这种方法将 最终使研究结果能够转化为临床，并可能改变 患者 我们将使用CRISPr/Cas9和Chip-seq等体外技术来剖析重要的信号通路 如缺氧诱导因子（HIF）。在确定适当的目标时，我们还将采用体外方法 并设计治疗方法来抵消修复缺陷。因此，定义非- 响应者将确定后续的新途径，并将导致改善的结果， 仅仅通过降低体温来靶向通路是永远无法实现的。了解级联如何 损伤反应的发生和关键调节剂在每个阶段将导致更多的合理治疗。