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.

抽象的： 白质损伤是最常见的新生儿脑损伤，导致过早的神经系统损伤 婴儿。这种损伤导致少突胶质细胞的局灶性和/或弥漫性损失，即髓鞘的细胞 脑。缺氧和炎症是该脆弱人群中常见和重要的危险因素， 没有可用的治疗选择。对新型治疗策略的制定构成重大挑战 对于新生儿中的脑损伤是安全的关注点。脱发创新的治疗性开发 在这个领域，我们专注于鉴定人类母体中存在的内源信号分子 母乳进一步发展为新生儿的安全有效疗法。我们确定了多种氧化的多氧化 人类母乳中的胆固醇（氧蛋白酶）促进少突胶质细胞命运规格 通过声波刺猬依赖的机制通过产后神经干细胞群体。遵循新生儿WMI， 母乳相关的氧甲醇的全身性给药逆转了脑室周围少突胶质细胞的丧失 并在我们的新生儿炎症WMI小鼠模型中挽救了相关的运动缺陷。我们的长期目标 是为了开发安全有效的疗法，以减轻新生儿WMI的神经系统缺陷。目的 该建议是测试20HC治疗在慢性缺氧模型中的疗效，并确定分子 诱导的寡聚发生机理。我们的中心假设是氧蛋白酶治疗将改善 缺氧诱导的新生儿WMI通过干细胞衍生的寡导dendogogenogenation诱导的髓鞘化并诱导 少突胶质细胞前体细胞（OPC）成熟。基本原理是确定氧甲醇的功效 缺氧动物模型中的疗法将导致新型疗法的重要发展，以治疗缺氧诱导的 新生儿脑损伤。在AMIS 1和2中，我们将测试新生小鼠20HC治疗的功效 慢性缺氧的模型。使用单独的遗传工具，我们可以确定两者的细胞行为 内源性神经干细胞（AIM 1）以及OPC（AIM 2）响应治疗。在我们的最后目标3中，我们 将探索氧蛋白酶诱导的翻译后蛋白质修饰对SOX10的影响。 Sox10是关键 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甲醇，所以 方法可能会进一步发展为一种新颖且安全的治疗策略，以减轻髓鞘损伤 那些在新生儿时期。对氧蛋白酶诱导的分子机制的全面理解 OPC的成熟可能支持成人髓磷脂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。