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

摘要 弥漫性脑白质损伤是一种脑损伤，通常发生在早产，是一种主要的 脑性瘫痪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。从死后的人类组织和啮齿动物中积累证据 模型提示胶质细胞成熟延迟是低氧诱导的结构性和 功能性神经异常。特别是，新生儿缺氧会导致胚胎发育迟缓 少突胶质细胞，中枢神经系统(CNS)的髓鞘形成胶质细胞，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和 胎儿期晚期和出生后早期的髓鞘形成，此时营养完全由母亲提供。 我们对促进正常中枢神经系统髓鞘形成的母源性因子了解不完全。 而且可以安全地给婴儿服用，以促进脑白质损伤的恢复。的目标是 本研究旨在了解天然糖醇肌醇在信号调节中的作用。 对于正常发育的髓鞘形成至关重要的途径，并确定补充剂 肌醇可促进新生儿慢性缺氧所致脑白质损伤的恢复。这个 中心假说是肌醇激活了肌醇磷脂信号通路，从而促进 发育过程中和白质损伤时少突胶质细胞的髓鞘形成。我们将在以下方面测试这一假设 利用体外和体内正常发育和慢性啮齿动物模型进行功能获得和丧失的研究 新生儿缺氧。目的1将测试少突胶质细胞摄取肌醇是否驱动髓鞘包裹 通过调节少突胶质细胞磷脂酰肌醇水平的发育。目标2将测试肌醇 直接作用于缺氧修复慢性缺氧新生儿髓鞘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本的 少突胶质细胞生物学以及新生儿脑白质损伤的潜在治疗方法。为了 在这些研究中，我将学习电子显微镜、质谱学和基于CRISPR的基因编辑 在我的赞助人陈博士的指导下。我还将接受关键职业发展方面的进一步培训 陈冯富珍博士和参与加州大学旧金山分校的演讲、科学写作和风采等技能 研讨会。我相信，完成这里描述的研究目标，我从 陈博士和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 成为学术界终身教职的独立研究员。

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.