Mechanisms of oxysterol-induced oligodendrogenesis

氧甾醇诱导少突胶质细胞发生的机制

• 批准号: 10295785
• 负责人: Eric J Benner
• 金额: $ 61.06万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295785
• 关键词: Acetylation; Adult; Affect; Alleles; Animal Model; Arginine; Biological Assay; Blindness; Brain; Brain Injuries; Cell Maturation; Cells; Cerebral Palsy; ChIP-seq; Child; Childhood; Cholesterol; Chronic; Cognitive; Complex; Data; Development; Diffuse; Disease; Dose; Environment; Epilepsy; Exposure to; Future; Generations; Genetic; Genome; Goals; Human; Human Milk; Hypoxia; Immunoprecipitation; In Vitro; Infant; Inflammation; Inflammatory; Injury; Intellectual functioning disability; Lead; Live Birth; Lysine; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Morphology; Motor; Multiple Sclerosis; Mutate; Myelin; Neonatal; Neonatal Brain Injury; Neurodevelopmental Deficit; Neurologic Deficit; Neurological outcome; Oligodendroglia; Outcome; Oxides; Peptides; Perinatal Brain Injury; Post-Translational Protein Processing; Premature Infant; Risk; Risk Factors; Role; SHH gene; Safety; Signaling Molecule; Site; Stroke; Testing; Therapeutic; Translating; Translations; Transmission Electron Microscopy; Traumatic Brain Injury; Vulnerable Populations; Work; brain tissue; care costs; cell behavior; disability; effective therapy; efficacy testing; genetic approach; hypoxia neonatorum; improved; in vivo; injury and repair; innovation; life time cost; motor deficit; mouse model; myelination; neonatal mice; neonatal period; neonate; nerve stem cell; nestin protein; novel; novel therapeutics; oligodendrocyte lineage; oligodendrocyte precursor; oligodendrocyte progenitor; postnatal; preclinical development; precursor cell; repaired; response; small molecule; smoothened signaling pathway; stem cell fate; stem cell population; stem cells; subventricular zone; therapeutic development; tool; transcription factor; treatment response; treatment strategy; white matter injury

Abstract: White matter injury is the most common neonatal brain injury leading to poor neurologic outcomes in premature infants. This injury results in both focal and/or diffuse losses of oligodendrocytes, the myelinating cells in the brain. Hypoxia and inflammation are common and important risk factors within this vulnerable population and there are no treatment options available. A significant challenge to the development of novel treatment strategies for brain injury in neonates is the appropriate concern for safety. To de-risk innovative therapeutic development in this field, we focused on the identification of endogenous signaling molecules present in human maternal breast milk to further develop into safe and effective therapies for neonates. We identified multiple oxidized cholesterols (oxysterols) in human maternal breast milk that promote oligodendrocyte fate specification in postnatal neural stem cell populations via a sonic hedgehog-dependent mechanism. Following neonatal WMI, systemic administration of breast milk-associated oxysterol reversed the loss of periventricular oligodendrocytes and rescued associated motor deficits in our neonatal inflammatory WMI mouse model. Our long-term objective is to develop safe and effective therapy that mitigates the neurologic deficits of neonatal WMI. The objective of this proposal is to test the efficacy of 20HC therapy in a chronic hypoxia model and determine the molecular mechanism(s) of induced oligodendrogenesis. Our central hypothesis is that oxysterol therapy will improve myelination in hypoxia-induced neonatal WMI through stem cell-derived oligodendrogenesis and induced oligodendrocyte precursor cell (OPC) maturation. The rationale is that determining the efficacy of oxysterol therapy in animal models of hypoxia will lead to critical development of novel therapies to treat hypoxia-induced neonatal brain injuries. In Amis 1 & 2 this proposal we will test the efficacy of 20HC therapy in a neonatal mouse model of chronic hypoxia. Using separate genetic tools, we can determine the cellular behavior of both endogenous neural stem cells (Aim 1) as well as OPCs (Aim 2) in response to therapy. In our final Aim 3, we will explore the impact of oxysterol-induced posttranslational protein modifications on Sox10. Sox10 is a critical transcription factor that regulates oligodendrocyte maturation. Because oxysterols are found in breast milk, this approach may be further developed into a novel and safe therapeutic strategy to mitigate myelin injuries including those in the neonatal period. A comprehensive understanding of the molecular mechanisms of oxysterol-induced OPC maturation may support further testing in models of adult myelin disorders including, multiple sclerosis (MS), traumatic brain injury, and stroke.

摘要： 脑白质损伤是早产儿最常见的导致神经预后不良的新生儿脑损伤 婴儿。这种损伤会导致局灶性和/或弥漫性少突胶质细胞的丢失，即 大脑。缺氧和炎症是这一脆弱人群中常见的重要危险因素， 目前还没有可用的治疗方案。开发新的治疗策略面临的重大挑战 对于新生儿的脑损伤是适当的安全性考虑。降低创新治疗开发的风险 在这一领域，我们专注于鉴定存在于人类母体中的内源性信号分子。 母乳将进一步发展成为安全有效的新生儿治疗方法。我们发现了多处氧化 人母乳中促进少突胶质细胞命运规范的胆固醇(氧化甾醇) 通过声学刺猬依赖机制的出生后神经干细胞群体。在新生儿WMI之后， 全身应用母乳相关的氧固醇逆转脑室周围少突胶质细胞的丢失 并在我们的新生儿炎症性WMI小鼠模型中挽救了相关的运动缺陷。我们的长期目标 是开发安全有效的治疗方法，减轻新生儿WMI的神经功能缺陷。的目标是 这项建议是在慢性缺氧模型中测试20HC治疗的有效性，并确定分子水平 诱导少突胶质细胞发生的机制(S)。我们的中心假设是羟类固醇治疗将会改善 低氧诱导的新生儿WMI中干细胞来源的少突胶质细胞和诱导的髓鞘形成 少突胶质前体细胞(OPC)成熟。其基本原理是确定羟类固醇的疗效 低氧动物模型的治疗将导致治疗低氧诱导的新疗法的关键发展 新生儿脑损伤。在AMIS1和2中，我们将在新生小鼠身上测试20HC治疗的疗效 慢性缺氧模型。使用不同的基因工具，我们可以确定两者的细胞行为 内源性神经干细胞(目标1)以及OPC(目标2)对治疗的反应。在我们的最终目标3中，我们 将探索氧固醇诱导的翻译后蛋白质修饰对Sox10的影响。Sox10是一个关键的 调节少突胶质细胞成熟的转录因子。因为在母乳中发现了氧化类固醇，所以 方法可以进一步发展为一种新的和安全的治疗策略来减轻髓鞘损伤，包括 那些处于新生儿期的人。全面了解氧化甾醇诱导的分子机制 OPC的成熟可能支持对成人髓鞘疾病模型的进一步测试，包括多发性硬化症 (Ms)、创伤性脑损伤和中风。