Precision Therapy for Neonatal Brain Injury

新生儿脑损伤的精准治疗

• 批准号: 10304137
• 负责人: Donna M. Ferriero
• 金额: $ 71.33万
• 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/10304137
• 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.

项目摘要/摘要部分 新生儿脑损伤是导致死亡和残疾的重要原因，其途径包括氧化应激、 炎症和兴奋性毒性导致损伤长期进展。疗法有 传统上在损伤的早期阶段针对单个通路，但在损伤后期针对通路 伤害反应可能也更有效。治疗性低温 (TH)，同时是标准护理 对于缺氧缺血性脑病 (HIE)，仅对 60% 的婴儿提供保护。首要的 假设 TH 后大脑的代谢状态在不同人群之间存在显着差异 低体温反应者和无反应者。我们将使用质子和 超极化碳 13 光谱，然后研究细胞途径以识别更精确和 个体化治疗方法。我们将使用出生后第 9 天的小鼠并跟踪它们的损伤情况 进化。本提案中概述的研究反映了一种创新和系统的研究方法 新生儿 HI 脑损伤是因为它们结合了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，这将提供信息并被 由人体临床研究提供信息。利用遗传细胞方法分析损伤的组成部分 在特定的细胞室中专门删除/破坏响应将使我们能够评估 体内神经血管生态位的好处。我们将广泛探究 HIF 依赖性信号通路 损伤后使用 ChIP-Seq。总之，这些遗传工具将使我们能够探索分子 HI 的体外和体内调节，以更好地识别更合适的治疗分子靶点 最需要它们的人。通过使用传统方法研究细胞水平上对 HI 的反应 使用 MR 光谱法进行生化分析和大脑的整体水平，我们的目标是在两者之间建立联系 可以非侵入性检测到的特定细胞变化和代谢变化。这种方法将 最终将研究结果转化为临床，并可能改变治疗的管理 患者。 我们将利用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）。当我们确定合适的目标时，我们还将使用体外方法 并设计疗法来抵消修复缺陷。因此，定义非非大脑代谢特征 响应者将确定随后的新目标途径，并将导致改善的结果，从而可以 仅仅通过降低体温来靶向途径是不可能实现的。了解级联如何 损伤反应的发生和每个阶段的关键调节剂将导致更合理的治疗。