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

描述(由申请人提供)： 项目概述：这是一份临床科学家指导研究职业发展奖提案的重新提交。拟议的培训将为一名年轻的儿科神经病学教员做好准备，成为翻译神经科学研究领域的独立研究员，专注于白质发育的围产期障碍。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。这项建议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、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。在法特米博士的儿科神经学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丰富的临床研究经验；然而，他还需要接受设计基于细胞的白质障碍疗法所需的基本科学技术方面的额外培训。这项提案中概述的指导研究和教学经验将建立在候选人之前的临床和研究经验的基础上，通过使用白质损伤的活体小鼠模型来测试移植神经胶质前体细胞的恢复效果。法特米博士开发了一种新的围产期白质损伤(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。他还分离了小鼠的神经胶质前体细胞，并证明了这些细胞在新生期被植入小鼠的白质后仍能存活。根据审查员的建议，对这项提案的三个具体目标进行了彻底修订。具体地说，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小鼠模型的细胞存活率。目的2利用分子生物学技术调控成纤维细胞生长因子受体在胶质前体细胞中的表达，以促进这些细胞在体外和体内分化为成熟的少突胶质细胞。目的3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发育的能力。这项为期5年的计划将包括动物研究的课程作业和非正式培训，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。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学和患有白质障碍的较大儿童的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建立独立研究生涯提供了理想的环境，最终将把基础科学进步转化为新的疗法。 公共卫生相关性： 项目简介：围产期白质损伤是早产婴儿脑性瘫痪的最常见原因，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脑白质损伤。这项研究计划侧重于在动物模型中开发针对这种情况的基于细胞的新疗法，并将为未来具有潜在临床意义的脑性瘫痪儿童研究奠定基础。

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.