Enhanced EGF Receptor Signaling Prevents White Matter Injury in Perinatal Hypoxia

描述（由申请人提供）：该指导临床科学家研究职业发展奖将为儿童神经学教师的学术生涯做好准备，使其成为多学科转化神经科学研究的独立研究者，重点研究脑白质损伤和早期脑损伤后的恢复。这项研究将在国家儿童医学中心神经科学中心进行。弥漫性脑室周围白质损伤（DWMI）是早产儿脑损伤的一种主要形式，可导致长期认知、感觉运动和行为缺陷。目前还没有特定的靶向疗法来促进白质的恢复。本研究的重点是在大脑内源性祖细胞上发现的表皮生长因子受体（EGFR），以及通过特异性靶向治疗增强其信号传导是否能促进白质少突胶质细胞的恢复。Scafidi博士是一名儿童神经学家，主要关注新生儿神经病学以及这些儿童的长期护理和管理。在Scafidi博士作为儿童神经学家接受培训期间，他获得了发育神经生物学、临床神经生理学和神经影像学领域的经验。然而，Scafidi博士需要在基础神经科学技术方面接受额外的培训，以研究通过多学科方法（包括细胞、分子、代谢和生理学技术以及行为研究）增强内源性EGFR信号的特定靶向治疗是否能促进恢复。Scafidi博士正在使用一种新的慢性围产期缺氧小鼠模型，这种模型会导致与人类早产儿相似的神经病理和神经行为变化。本研究提出的目标是解决EGFR信号增强在损伤后大脑发育关键时期刺激EGFR+祖细胞内源性反应，促进缺氧后细胞、功能和行为恢复的总体假设。在目标1中，Scafidi博士将确定EGF在慢性围产期缺氧后少突胶质细胞再生和发育性髓鞘形成中的作用。在Aim 2中，他将确定慢性围产期缺氧对轴突完整性造成的功能缺陷，以及在少突胶质细胞中过度表达EGFR或用EGFR配体治疗是否促进功能恢复。最后，在第三个目标中，Scafidi博士将定义由慢性围产期缺氧引起的长期行为缺陷，并确定EGFR信号的增强是否能预防这些缺陷。这个为期5年的项目将包括由优秀的导师和顾问团队提供的教学和研究培训。Scafidi博士75%的时间将用于研究，其余时间将用于与新生儿神经学和早产儿长期护理相关的临床活动。在其主要导师的指导下，神经科学研究中心是候选人在多学科和协作环境中发展成为独立研究者的理想环境。

DESCRIPTION (provided by applicant): This Mentored Clinical Scientist Research Career Development Award will prepare a child neurology faculty member for an academic career as an independent investigator in multidisciplinary translational neuroscience research with a focus on white matter injury and recovery after premature brain injury. This research will be conducted in the Center for Neuroscience at Children's National Medical Center. Diffuse periventricular white matter injury (DWMI) is a major form of brain injury in children born very premature and results in long-term cognitive, sensori-motor and behavioral deficiencies. There are currently no specific targeted therapies that promote white matter recovery. This proposal focuses on the Epidermal Growth Factor Receptors (EGFR) found on endogenous progenitor cells in the brain and whether enhancing their signaling with specific targeted therapies promote recovery of white matter oligodendrocytes. Dr Scafidi is a child neurologist with a primary focus on neonatal neurology and the long-term care and management of these children. During Dr Scafidi's training as a child neurologist, he gained experience in the fields of developmental neurobiology, clinical neurophysiology and neuroimaging. However, Dr Scafidi needs additional training in basic neuroscience techniques to investigate whether specific targeted therapies that enhance endogenous EGFR signaling promotes recovery using a multidisciplinary approach that involves cellular, molecular, metabolic and physiology techniques as well as behavioral studies. Dr Scafidi is using a novel mouse model of chronic perinatal hypoxia that results in neuropathological and neurobehavioral changes similar to those found in human very preterm infants. The proposed aims of this study will address the overall hypothesis that enhanced EGFR signaling stimulates the endogenous response of EGFR+ progenitor cells during a critical period in brain development after injury and promotes cellular, functional and behavioral recovery after hypoxia. In aim 1, Dr Scafidi will determine the role of EGF on oligodendrocyte regeneration and developmental myelination after chronic perinatal hypoxia. In Aim 2, he will determine the functional deficits caused by chronic perinatal hypoxia on axon integrity and whether over-expression of EGFR in oligodendrocytes or treatment with EGFR ligand promotes functional recovery. Finally, in the third aim Dr Scafidi will define the long-term behavioral deficits induced by chronic perinatal hypoxia and determine whether enhanced EGFR signaling prevents these deficits. This 5-year program will include didactic and research training from an excellent team of mentors and advisors. 75% of Dr Scafidi's time will be devoted to research, with the remaining time devoted to the clinical activities related to neonatal neurology and long-term care of those born prematurely. The Center for Neuroscience Research under the direction of his primary mentor is the ideal setting for a candidate to develop into an independent investigator in a multidisciplinary and collaborative environment.