Enhanced EGF Receptor Signaling Prevents White Matter Injury in Perinatal Hypoxia

增强的 EGF 受体信号传导可预防围产期缺氧时的白质损伤

基本信息

批准号：
8436277
负责人：
Joseph Scafidi
金额：
$ 17.81万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8436277
关键词：
Address Adult Astrocytes Axon Behavior Behavioral Brain Brain Injuries Bromodeoxyuridine CSPG4 gene Cell Lineage Cells Child Childhood Childhood Injury Chronic Clinical Cognitive Complex Cytoskeleton DTR gene Data Demyelinations Development Diffuse EGF gene EGFR Protein Overexpression Environment Epidermal Growth Factor Receptor Faculty Genetic Glial Fibrillary Acidic Protein Goals Human Hypoxia Immunohistochemistry Impaired cognition In Vitro Infant Injury K-Series Research Career Programs Laboratories Ligands Long-Term Care Maps Medical center Mentors Metabolic Modeling Molecular Motor Motor Skills Mus NMR Spectroscopy Natural regeneration Neonatal Neurocognitive Neurologist Neurology Neurosciences Neurosciences Research Oligodendroglia Oligonucleotides Outcome Pediatric Neurology Perinatal Brain Injury Perinatal Hypoxia Periventricular white matter injury Physiologic pulse Physiological Physiology Population Pregnancy Premature Birth Premature Infant Proliferating Public Health Receptor Signaling Recovery Recovery of Function Reporter Research Research Personnel Research Training Role Running Scientist Signal Pathway Signal Transduction Stem cells Structure Techniques Testing Time Training Transgenic Mice Walking base behavior test behavioral deficiency career critical period design developmental neurobiology experience in vivo interdisciplinary approach member mouse model multidisciplinary myelination neurobehavioral neuroblast neuroimaging neurophysiology novel overexpression premature prevent progenitor programs protein expression public health relevance repaired research study response response to injury skills subventricular zone translational neuroscience white matter white matter injury

项目摘要

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.

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一名儿童神经病学教员做好学术生涯的准备，作为多学科转化神经科学研究的独立研究者，重点关注白质损伤和过早脑损伤后的恢复。这项研究将在国家儿童医学中心的神经科学中心进行。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，会导致长期认知、感觉运动和行为缺陷。目前尚无促进白质恢复的特异性靶向疗法。该提案的重点是大脑内源性祖细胞上发现的表皮生长因子受体（EGFR），以及通过特定的靶向治疗增强其信号传导是否可以促进白质少突胶质细胞的恢复。 Scafidi 博士是一名儿童神经科医生，主要研究新生儿神经病学以及这些儿童的长期护理和管理。 Scafidi 博士在接受儿童神经科医生培训期间，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 博士需要接受基础神经科学技术方面的额外培训，以利用涉及细胞、分子、代谢和生理学技术以及行为研究的多学科方法来研究增强内源 EGFR 信号传导的特定靶向疗法是否可以促进康复。 Scafidi 博士正在使用一种新型的慢性围产期缺氧小鼠模型，该模型会导致与人类早产儿相似的神经病理学和神经行为变化。本研究的拟议目标将解决总体假设，即增强的 EGFR 信号传导会在损伤后大脑发育的关键时期刺激 EGFR+ 祖细胞的内源性反应，并促进缺氧后细胞、功能和行为的恢复。在目标 1 中，Scafidi 博士将确定 EGF 对慢性围产期缺氧后少突胶质细胞再生和发育性髓鞘形成的作用。在目标 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，以及少突胶质细胞中 EGFR 的过度表达或 EGFR 配体治疗是否会促进功能恢复。最后，在第三个目标中，Scafidi 博士将定义慢性围产期缺氧引起的长期行为缺陷，并确定增强的 EGFR 信号传导是否可以预防这些缺陷。这个为期 5 年的计划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，其余时间用于与新生儿神经病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的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。