Precision Therapy for Neonatal Brain Injury

新生儿脑损伤的精准治疗

• 批准号: 10516041
• 负责人: Donna M. Ferriero
• 金额: $ 95.1万
• 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/10516041
• 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; Non-Invasive Detection; 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; protective pathway; 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 新生儿脑损伤是死亡和残疾的重要原因，并具有氧化应激的途径， 炎症和兴奋性毒性会导致长时间的损害。疗法有 在受伤的早期阶段，经典针对的单个途径，但后来靶向途径 伤害反应可能是有效的。治疗性体温过低（TH），同时是护理标准 对于低氧缺血性脑病（HIE），仅在60％的婴儿中提供保护。总体 假设是，在TH之后，大脑的代谢状态明显不同 体温过低的反应者和无反应者。我们将使用质子和 超极化碳13光谱法，然后研究细胞途径，以识别更精确的和 个性化的治疗方法。我们将使用出生后第9天的小鼠，并因受伤跟随它们 进化。该提案中概述的研究反映了对研究的创新和系统的方法 新生儿中的脑损伤是因为它们结合了先进的代谢成像技术（质子和 碳光谱法和细胞信号研究，重点是HIF信号传导，这既可以告知又 由人类临床研究得知。利用遗传细胞方法，其中损伤成分 在特定的单元室中明确删除/中断响应将使我们能够评估 体内神经血管生态位的好处。我们将广泛询问HIF依赖性信号通路 使用Chip-seq受伤后。这些遗传工具在一起将使我们能够探索分子 在体外和体内调节HI，以更好地识别更合适的分子靶标的 个人最需要他们。通过使用传统的蜂窝级调查对HI的响应 使用MR光谱法，我们的目标是在大脑中的生化测定和全球水平 特定的细胞变化和代谢变化，可以非侵入性地检测到。这种方法会 最终允许调查结果转化为诊所，并有可能改变 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 像缺氧诱导因子（HIF）。当我们确定适当的目标时，我们还将使用Invitro方法 并设计疗法以抵消不足的维修。因此，定义非脑代谢特征 响应者将确定随后的新型目标途径，并将带来改善的结果 仅仅通过仅通过低温靶向途径就可以实现。了解级联如何 发生伤害反应，每个阶段的关键调节剂将导致更多的理由疗法。