Neurotrophin Treatment for Pediatric Brain Injury

描述（由申请人提供）：候选人的目标是在来自宾夕法尼亚大学和德雷塞尔大学医学院的杰出导师和咨询委员会的指导下，成为一名独立的儿科创伤性脑损伤（TBI）临床医生和科学家，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拥有丰富的资源和人员，因此这位初级研究员将更加熟练地掌握本研究计划中概述的实验室技能、科学写作、研究设计和实验方法。许医生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师，负责治疗创伤性脑损伤（TBI）儿童。尽管创伤性脑损伤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。创伤性脑损伤后，大脑似乎会短暂增加内源性神经营养因子分子，如胰岛素样生长因子I （IGF-I）和神经生长因子（NGF），它们在儿童大脑中的表达最高，通过促进树突生长、突触效能和抑制与创伤性轴突损伤有关的钙蛋白酶，对恢复至关重要。本研究通过临床相关的儿科大鼠闭合性颅脑损伤模型，目的是证明外源性给药这些营养因子可以促进树突生长和突触效能，抑制calpain2介导的轴突损伤，从而预防慢性认知缺陷。这些研究与公共卫生非常相关，因为它们将为未来的研究提供理论基础，以开发新的转化疗法来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。

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.