Myo-inositol regulation of myelination in development and hypoxic newborn brain injury

肌醇对发育中髓鞘形成和缺氧新生儿脑损伤的调节

• 批准号: 9920596
• 负责人: SARAH E RAISSI
• 金额: $ 7.01万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920596
• 关键词: Ablation; Academia; Address; Adult; Autopsy; Biological Assay; Biology; Biosensor; Brain; Brain Injuries; CRISPR/Cas technology; Cell Count; Cell physiology; Cells; Cerebral Palsy; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Cognitive; Cognitive deficits; Complication; Data; Defect; Development; Developmental Disabilities; Diffuse; Electron Microscopy; Environment; Event; Genes; Goals; Growth; Human; Human Milk; Hypoxia; Hypoxic Brain Damage; Image; Impairment; In Vitro; Infant; Injury; Inositol; Knock-out; Knockout Mice; Learning; Length; Life; Mass Spectrum Analysis; Measures; Mediating; Membrane; Mentorship; Mothers; Motor; Mus; Myelin; Myelin Sheath; Neonatal; Neuraxis; Neurodevelopmental Disorder; Neuroglia; Neurologic; Neurons; Newborn Infant; Nutraceutical; Nutrient; Oligodendroglia; Oxygen; Pathway interactions; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphorylation; Premature Birth; Premature Infant; Prevention; Recovery; Recovery of Function; Regulation; Research; Research Personnel; Rodent Model; Role; Signal Pathway; Signal Transduction; Structure; Sugar Alcohols; Supplementation; Testing; Therapeutic; Thick; Tissue Model; Training; Walking; Wild Type Mouse; Writing; base; career development; cognitive function; conditional knockout; deprivation; experimental study; extracellular; gain of function; human tissue; hypoxia neonatorum; improved; in vivo; insight; loss of function; lung development; motor deficit; mouse model; myelination; neonatal brain; nervous system disorder; newborn brain injury; novel; nutrition; nutritional supplementation; object recognition; oligodendrocyte myelination; postnatal; prenatal; repaired; skill acquisition; sugar; tenure track; therapeutic target; uptake; white matter; white matter damage; white matter injury

Abstract Diffuse white matter damage, a type of brain injury, commonly occurs with premature birth and is a leading cause of cerebral palsy and neurodevelopmental disorders. This type of brain injury is often caused by hypoxia due to immature lung development. Accumulating evidence from both postmortem human tissue and rodent models suggests delay of glial maturation is a major underlying cause of hypoxia-induced structural and functional neurological abnormalities. In particular, neonatal hypoxia causes delayed maturation of oligodendrocytes, the myelin-forming glia of the central nervous system (CNS), and results in myelin defects and motor and cognitive abnormalities. Human infants typically undergo extensive glial maturation and myelination during late prenatal and early postnatal life, when nutrition can be supplied solely by the mother. We have an incomplete understanding of maternally-derived factors that contribute to normal CNS myelination and which could be safely administered to infants to promote recovery from white matter injury. The goal of this research is to understand the role of the natural sugar alcohol myo-inositol in regulating signaling pathways that are essential for normal developmental myelination, and to determine whether supplementation of myo-inositol can promote recovery from white matter injury caused by chronic neonatal hypoxia. The central hypothesis is that myo-inositol activates phosphoinositide signaling pathways that promote oligodendrocyte myelination during development and in white matter injury. We will test this hypothesis in gain- and loss-of-function studies using in vitro and in vivo rodent models of normal development and chronic neonatal hypoxia. Aim 1 will test whether oligodendrocyte uptake of myo-inositol drives myelin wrapping during development by modulating oligodendrocyte phosphoinositide levels. Aim 2 will test whether myo-inositol rescues myelin defects and promotes functional recovery in chronic neonatal hypoxia by acting directly on oligodendrocytes. Upon completion these studies will have important implications both for understanding basic oligodendrocyte biology as well as for potential therapeutics for neonatal white matter injury. In order to conduct these studies, I will learn electron microscopy, mass spectrometry, and CRISPR-based gene editing under the guidance of my sponsor, Dr. Chan. I will also receive further training in critical career development skills such as presentations, scientific writing, and grantsmanship from Dr. Chan and by participating in UCSF seminars. I am confident that completion of the research goals described here, the mentorship I receive from Dr. Chan, and the rigorous research environment at UCSF will enable me to achieve my long-term goal of becoming a tenure-track independent investigator in academia.

抽象的 弥漫性白质损伤是一种脑损伤，常见于早产，是导致早产的主要原因 脑瘫和神经发育障碍的原因。这种类型的脑损伤通常是由缺氧引起的 由于肺部发育不成熟。积累来自死后人体组织和啮齿动物的证据 模型表明，神经胶质成熟的延迟是缺氧引起的结构和功能的主要根本原因。 功能性神经异常。特别是新生儿缺氧会导致发​​育迟缓。 少突胶质细胞，中枢神经系统 (CNS) 的髓磷脂形成神经胶质细胞，并导致髓磷脂缺陷 以及运动和认知异常。人类婴儿通常会经历广泛的神经胶质成熟和 产前晚期和产后早期的髓鞘形成，此时营养只能由母亲提供。 我们对促进正常中枢神经系统髓鞘形成的母源因素还不完全了解 并且可以安全地给予婴儿以促进白质损伤的恢复。目标是 这项研究旨在了解天然糖醇肌醇在调节信号传导中的作用 正常发育髓鞘形成所必需的途径，并确定是否补充 肌醇可促进新生儿慢性缺氧引起的脑白质损伤的恢复。这 中心假设是肌醇激活磷酸肌醇信号通路，从而促进 发育过程中和白质损伤期间的少突胶质细胞髓鞘形成。我们将在 使用正常发育和慢性的体外和体内啮齿动物模型进行功能获得和丧失的研究 新生儿缺氧。目标 1 将测试少突胶质细胞对肌醇的摄取是否驱动髓磷脂包裹 通过调节少突胶质细胞磷酸肌醇水平来发育。目标 2 将测试肌醇是否 通过直接作用于新生儿慢性缺氧，挽救髓磷脂缺陷并促进功能恢复 少突胶质细胞。完成后，这些研究将对理解基础知识产生重要影响。 少突胶质细胞生物学以及新生儿白质损伤的潜在治疗方法。为了 进行这些研究时，我将学习电子显微镜、质谱和基于 CRISPR 的基因编辑 在我的赞助商陈博士的指导下。我还将接受关键职业发展方面的进一步培训 陈博士以及参与加州大学旧金山分校的项目所提供的演讲、科学写作和资助等技能 研讨会。我有信心完成这里描述的研究目标，以及我收到的指导 陈博士，加州大学旧金山分校严谨的研究环境将使我能够实现我的长期目标 成为学术界的终身教授独立研究者。