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

项目总结 这是指导临床科学家研究职业发展奖提案的重新提交。这个 拟议的培训将使一名年轻的儿科神经病学教员为独立职业生涯做好准备 翻译神经科学研究领域的研究员，专注于围产期白质障碍 发展。这项研究将在肯尼迪·克里格的雨果·莫泽研究所和 约翰霍普金斯大学细胞工程研究所和神经病学系 医学。这项提案侧重于新生儿获得性脑白质损伤的新疗法，作为 影响婴儿和儿童的获得性、新陈代谢和遗传白质障碍的范例。 这组障碍是基于大脑的认知和运动障碍的主要原因。在法特米医生的 在接受过儿科神经病学的医学和临床培训后，在 神经化学、神经遗传学和磁共振成像领域；然而，他需要更多 为白质疾病设计基于细胞的疗法所需的基本科学技术培训。这个 这份提案中概述的有指导的研究和授课经验将建立在候选人之前的 用白质损伤小鼠体内模型测试恢复剂的临床和研究体会 神经胶质前体细胞移植的效果。法特米博士开发了一种新的围产期小鼠模型 脑白质损伤(PWMI)复制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身上观察到的特征。他还分离了小鼠神经胶质前体细胞，并 已经证明，这些细胞在新生期间被植入小鼠的白质后仍能存活 句号。这项建议的三个具体目标已根据建议进行了彻底修订 评论家的意见。具体地说，目标1现在涉及确定神经胶质前体细胞的最佳时间 提高PWMI小鼠模型细胞存活率的移植。目标2涉及调制 用分子生物学技术检测成纤维细胞生长因子受体在胶质前体细胞中的表达 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质损伤和刺激 新白质的发育。这项为期5年的计划将包括课程作业和动物的非正式培训。 研究，包括先进的核磁共振和组织学技术，以及细胞培养和细胞工程 方法：研究方法。学员大约80%的时间将用于研究，其中20%的时间用于 与新生儿神经病学相关的临床活动和对患有白质障碍的大龄儿童的护理。这个 肯尼迪·克里格研究所和约翰·霍普金斯大学医学院为 建立独立研究事业的候选人，最终将把基础科学进展转化为 新奇的疗法。

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.