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.

摘要 弥漫性白色物质损伤是一种脑损伤，通常发生在早产中， 脑瘫的病因是什么？这种类型的脑损伤往往是由缺氧引起的 由于肺部发育不成熟。从死后的人体组织和啮齿动物身上收集证据 模型表明，胶质细胞成熟的延迟是缺氧诱导的结构和 功能性神经异常特别是，新生儿缺氧会导致 少突胶质细胞，中枢神经系统（CNS）的髓鞘形成神经胶质细胞，并导致髓鞘缺陷 以及运动和认知异常人类婴儿通常经历广泛的神经胶质成熟， 在出生前晚期和出生后早期，当营养可以完全由母亲提供时，髓鞘形成。 我们对促进正常中枢神经系统髓鞘形成的母源性因素了解不完全 并且可以安全地给予婴儿以促进白色物质损伤的恢复。的目标 本研究旨在了解天然糖醇肌醇在信号转导中的作用 这些途径对于正常的髓鞘形成发育至关重要，并确定补充 结论：肌醇对新生儿慢性缺氧所致的白色损害有促进作用。的 中心假设是肌醇激活磷酸肌醇信号通路， 发育过程中和白色物质损伤中的少突胶质细胞髓鞘形成。我们将测试这个假设， 使用正常发育和慢性发育的体外和体内啮齿动物模型进行的功能获得和丧失研究 新生儿缺氧目的1将测试是否少突胶质细胞摄取肌醇驱动髓鞘包裹过程中 通过调节少突胶质细胞磷酸肌醇水平来促进发育。目标2将测试肌醇是否 通过直接作用于新生儿慢性缺氧， 少突胶质细胞这些研究一旦完成，将对理解基本的 少突胶质细胞生物学以及用于新生儿白色物质损伤的潜在治疗。为了 进行这些研究，我将学习电子显微镜，质谱，和基于CRISPR的基因编辑 在我的担保人陈医生的指导下我还将接受关键职业发展方面的进一步培训 技能，如演示文稿，科学写作，并从陈博士和参加加州大学旧金山分校的granisation 研讨会等我相信，完成这里所描述的研究目标，我从导师那里得到的指导， 博士陈，和加州大学旧金山分校严格的研究环境将使我能够实现我的长期目标， 成为学术界的终身独立调查员