Study of White Matter Development in a Rodent Model of Perinatal Brain Injury

项目摘要 这是指导临床科学家研究职业发展奖提案的重新提交。的 拟议的培训将准备一个年轻的儿科神经学教员的职业生涯作为一个独立的 转化神经科学研究领域的调查员，专注于白色物质的围产期疾病 发展这项研究将在肯尼迪克里格的雨果莫泽研究所和 约翰霍普金斯大学神经科学学院的细胞工程研究所和神经病学系 药该提案的重点是新生儿获得性白色损伤的新疗法， 这是影响婴儿和儿童的白色物质的获得性、代谢性和遗传性疾病的范例。 这类疾病是大脑认知和运动障碍的主要原因。在法特米博士 在儿科神经病学的医学和临床培训，他获得了相当多的临床研究经验， 神经化学，神经遗传学和磁共振成像领域;然而，他需要额外的 为白色物质紊乱设计细胞疗法所需的基础科学技术培训。的 本提案中概述的指导研究和教学经验将建立在候选人以前的 通过使用白色物质损伤的体内小鼠模型来测试恢复性的临床和研究经验 胶质前体细胞移植的影响。Fatemi博士开发了一种新的围产期小鼠模型， 白色物质损伤（PWMI）复制了显著的组织病理学和磁共振成像 在患有这种疾病的人类婴儿中观察到的特征。他还分离出了小鼠神经胶质前体细胞， 已经证明，这些细胞在新生期植入小鼠的白色物质中时存活， 期该提案的三个具体目标已根据建议进行了彻底修订 的评论家。具体来说，目标1现在涉及确定神经胶质前体细胞的最佳时间， 在PWMI的小鼠模型中改善细胞存活的移植。目标2涉及调节 使用分子生物学技术在神经胶质前体中表达成纤维细胞生长因子受体， 促进这些细胞在体外和体内分化为成熟的少突胶质细胞。目标3涉及 评估移植的神经胶质前体细胞修复白色物质损伤和刺激神经胶质细胞增殖的能力。 新的白色物质的发展。这个为期5年的计划将包括课程和非正式培训动物 研究，包括先进的MRI和组织学技术，以及细胞培养和细胞工程 方法.大约80%的受训者的时间将用于研究，20%的时间用于 与新生儿神经病学和患有白色疾病的大龄儿童的护理相关的临床活动。的 肯尼迪克里格研究所和约翰霍普金斯大学医学院为 候选人建立一个独立的研究生涯，最终将基础科学的进步转化为 新疗法

PROJECT SUMMARY This is a resubmission of a Mentored Clinical Scientist Research Career Development Award proposal. The proposed training will prepare a young pediatric neurology faculty member for a career as an independent investigator in the field of translational neuroscience research, focusing on perinatal disorders of white matter development. This research will be performed at the Hugo Moser Research Institute at Kennedy Krieger and at the Institute for Cell Engineering and the Department of Neurology at the Johns Hopkins University School of Medicine. This proposal focuses on novel therapies for acquired white matter injuries in neonates, as a paradigm for the acquired, metabolic and genetic disorders of white matter that affect infants and children. This group of disorders is a major cause of brain-based cognitive and motor disabilities. During Dr. Fatemi's medical and clinical training in pediatric neurology, he gained considerable clinical research experience in the fields of neurochemistry, neurogenetics and magnetic resonance imaging; however, he needs additional training in the basic science techniques needed to design cell-based therapies for white matter disorders. The mentored research and didactic experiences outlined in this proposal will build on the candidate's previous clinical and research experiences by using an in vivo mouse model of white matter injury to test the restorative effects of transplantation of glial precursor cells. Dr. Fatemi has developed a novel mouse model of perinatal white matter injury (PWMI) that replicates the salient histopathological and magnetic resonance imaging features observed in human infants with this condition. He has also isolated mouse glial precursor cells, and has demonstrated that these cells survive when implanted in the white matter of mice during the neonatal period. The three specific aims for this proposal have been thoroughly revised, in keeping with the suggestions of the reviewers. Specifically, Aim 1 now involves determining the optimum time of glial precursor cell transplantation that improves cell survival in a mouse model of PWMI. Aim 2 involves modulating the expression of fibroblast growth factor receptors in glial precursors using molecular biological techniques to improve the in vitro and in vivo differentiation of these cells into mature oligogodendrocytes. Aim 3 involves assessing the ability of transplanted glial precursor cells to repair white matter injury and to stimulate the development of new white matter. This 5-year program will include coursework and informal training in animal research, including advanced MRI and histological techniques, as well as cell culture and cell engineering methods. Approximately 80% of the trainee's time will be spent on research, with 20% of his time devoted to clinical activities related to neonatal neurology and the care of older children with white matter disorders. The Kennedy Krieger Institute and the Johns Hopkins University School of Medicine provide an ideal setting for the candidate to establish an independent research career that will ultimately translate basic science advances into novel therapies.