Neurotrophin Treatment for Pediatric Brain Injury

描述（由申请人提供）：候选人的目标是通过与宾夕法尼亚大学和德雷克塞尔大学医学院的杰出导师和咨询委员会的培训，成为儿科创伤性脑损伤（TBI）的独立临床医生-科学家，他们是儿科TBI研究领域的权威。宾夕法尼亚大学和德雷克塞尔大学的环境资源和人员丰富，使这位初级研究员在本研究提案中概述的实验室技能，科学写作，研究设计和实验方法学方面变得更加轻松。Huh博士是宾夕法尼亚大学医学院费城儿童医院的儿科重症监护医生，负责照顾创伤性脑损伤（TBI）儿童。尽管TBI是儿童获得性残疾和死亡的头号原因，但在急性环境中只能提供支持性护理。头部受伤的儿童通常会留下慢性学习（认知）缺陷。TBI后，大脑似乎短暂增加称为神经营养因子的内源性分子，如胰岛素样生长因子I（IGF-I）和神经生长因子（NGF），其表达在儿科大脑中最高，并且通过促进树突生长、突触功效和抑制钙蛋白酶（涉及创伤性轴突损伤的蛋白酶）对恢复很重要。使用临床相关的模型，在小儿脑外伤，本研究的目的是证明这些营养因子的外源性管理可以增强树突状细胞的生长和突触的功效，并抑制钙蛋白酶介导的轴突损伤，以防止慢性认知功能障碍。这些研究与公共卫生非常相关，因为它们将为候选人开发新型转化疗法以抑制与慢性行为缺陷相关的细胞过程并增强头部受伤儿童的大脑恢复提供未来研究的依据。

DESCRIPTION (provided by applicant): The candidate's goal is to become an independent clinician-scientist in pediatric traumatic brain injury (TBI) by training with an outstanding group of mentors and an advisory committee from the University of Pennsylvania and Drexel University College of Medicine who are authorities in the field of pediatric TBI research. The environment at Penn and Drexel are rich with resources and personnel so that this junior investigator will become more facile with laboratory skills, scientific writing, research design and experimental methodology outlined in this research proposal. Dr. Huh is a pediatric critical care physician at Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, who takes care of children with traumatic brain injury (TBI). Despite the fact that TBI is the number one cause of acquired disability and death in children, only supportive care can be provided in the acute setting. Head-injured children are often left with chronic learning (cognitive) deficits. Following TBI, the brain appears to transiently increase endogenous molecules called neurotrophic factors such as Insulin-like growth factor I (IGF-I) and Nerve growth factor (NGF), whose expression is highest in the pediatric brain and important for recovery by promoting dendritic growth, synaptic efficacy, and inhibiting calpains, proteases implicated in traumatic axonal damage. Using a clinically relevant model of closed head injury in pediatric rats, the goals of this research proposal are to demonstrate that the exogenous administration of these trophic factors can enhance dendritic growth and synaptic efficacy, and inhibit calpain-mediated axonal injury to prevent chronic cognitive deficits. These studies are very relevant to public health because they will provide the rationale for future investigations for the candidate to develop novel translational therapies to inhibit cellular processes associated with chronic behavioral deficits and to enhance brain recovery in head-injured children.