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

描述（由申请人提供）： 项目总结：这是一个指导临床科学家研究职业发展奖提案的重新提交。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调查员在翻译神经科学研究领域，重点是围产期疾病的白色物质的发展。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医学院的细胞工程研究所和神经病学系进行。该提案侧重于新生儿后天性白色物质损伤的新疗法，作为影响婴儿和儿童的后天性、代谢和遗传性白色物质疾病的范例。这类疾病是大脑认知和运动障碍的主要原因。在Fatemi博士接受儿科神经病学的医学和临床培训期间，他在神经化学、神经遗传学和磁共振成像领域获得了相当多的临床研究经验;然而，他需要在设计白色疾病细胞疗法所需的基础科学技术方面接受额外培训。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临床和研究经验的基础上，通过使用体内小鼠白色物质损伤模型来测试神经胶质前体细胞移植的恢复效果。Fatemi博士开发了一种新的围产期白色物质损伤（PWMI）小鼠模型，该模型复制了在患有这种疾病的人类婴儿中观察到的显著组织病理学和磁共振成像特征。他还分离出了小鼠神经胶质前体细胞，并证明了这些细胞在新生期植入小鼠的白色物质中后能够存活。根据审查人员的建议，对该提案的三个具体目标进行了彻底修订。具体来说，目标1现在涉及确定神经胶质前体细胞移植的最佳时间，以提高PWMI小鼠模型中的细胞存活率。目的2是利用分子生物学技术调控胶质前体细胞中成纤维细胞生长因子受体的表达，以提高这些细胞在体外和体内向成熟少突胶质细胞的分化。目的3包括评估移植的胶质前体细胞修复白色物质损伤和刺激新白色物质发育的能力。这个为期5年的计划将包括动物研究的课程和非正式培训，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。受训者大约80%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护理相关的临床活动。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提供了一个理想的环境，以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的疗法。 公共卫生相关性： 项目叙述：围产期白色物质损伤是早产儿脑瘫的最常见原因，在美国每年影响数千名婴儿。目前还没有有效的干预措施来预防或修复围产期白色物质损伤。这项研究计划的重点是在这种疾病的动物模型中开发新型细胞疗法，并将为未来研究奠定基础，对脑瘫儿童具有潜在的临床意义。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE: Perinatal white matter injury is the most common cause of cerebral palsy in infants born prematurely affecting thousands of babies every year in the United States. There are currently no effective interventions to prevent or repair perinatal white matter injury. This research proposal focuses on the development of novel cell-based therapies in an animal model for this condition and will lay the foundation for future studies with potential clinical implications in children with cerebral palsy.