CSF LEVELS OF L1CAM AND AMYLOID PRECURSOR PROTEIN IN POST-HEMORRHAGIC HYDROCEPHAL

描述（由申请人提供）：本次职业发展奖（CDA）的候选人是一名儿科神经外科医生，对推进出血性早产脑积水（PHH）领域和改善患有这种疾病的婴儿的护理和预后有特殊兴趣。该提案中概述的严格的职业发展计划既有教学成分，也有博士实验室的指导科学培训。华盛顿大学的特里·因德尔和大卫·霍尔茨曼说。该计划以美国国立卫生研究院支持的跨学科研究中心和临床研究培训中心的优势为基础，将候选人的培训重点放在临床研究方法，脑脊液（CSF）蛋白质生物学，以及早产儿的神经发育和残疾方面。通过CDA获得的额外培训和技能将补充候选人以前的研究背景，并提供成为独立临床科学家所需的新专业知识。该建议的中心假设是脑脊液中神经发育蛋白L1CAM和淀粉样前体蛋白（APP）的水平在PHH中选择性升高，并且这些蛋白的持续升高与心室大小增加、脑室-腹膜（VP）分流需求和不良神经预后有关。本提案的具体目的是：1)比较对照组、PHH和其他神经系统疾病患者脑脊液L1CAM和APP的水平；2)明确脑脊液L1CAM、APP与PHH脑室大小的关系；3)确定18-24月龄phh相关CSF L1CAM和APP升高与神经发育结局的关系。候选人建议利用他在脑积水临床研究网络的参与，在华盛顿大学建立一个多机构新生儿脑脊液储存库。PHH患者的脑脊液L1CAM和APP水平将采用elisa检测，并与脑室内出血和其他早产儿常见神经系统疾病患者的水平进行比较。这些脑脊液蛋白与基于超声的心室大小测量之间的关系将被定义，并且脑脊液L1CAM和APP在识别需要VP分流的婴儿方面所提供的相对收益将被估计。最后，在矫正年龄18-24月龄时，使用Bayley婴儿发育量表iii评分来确定CSF L1CAM和APP水平与神经发育结局的关系。如果成功，这些研究将通过为开发脑脊液L1CAM和APP水平作为PHH相关神经功能障碍的标志物提供关键数据，推进PHH领域的发展。这些标志物最直接的好处是补充现有的基于图像的心室测量，以更好地为改善PHH婴儿预后的临床试验提供信息。

DESCRIPTION (provided by applicant): The candidate for this Career Development Award (CDA) is a pediatric neurosurgeon with a specific interest in advancing the field of post-hemorrhagic hydrocephalus of prematurity (PHH) and improving the care and outcomes of infants with this condition. The rigorous career development program outlined in this proposal has both didactic components and mentored scientific training in the laboratories of Drs. Terrie Inder and David Holtzman at Washington University. The proposed program builds on the strengths of the University's NIH-supported interdisciplinary research centers and the Clinical Research Training Center to focus the candidate's training on clinical research methodologies, cerebrospinal fluid (CSF) protein biology, and neurodevelopment and disability in the preterm infant. The additional training and skills acquired through this CDA will complement the candidate's previous research background and provide new expertise necessary to become an independent clinician-scientist. The central hypotheses of this proposal are that CSF levels of the neurodevelopment proteins L1CAM and amyloid precursor protein (APP) are selectively increased in PHH, and that protracted elevations of these proteins are associated with increased ventricular size, ventriculoperitoneal (VP) shunt requirement, and adverse neurological outcome. The Specific Aims of this proposal are to: 1) compare the levels of CSF L1CAM and APP in control, PHH, and other neurological conditions; 2) define the association between CSF L1CAM and APP and ventricular size in PHH; and 3) determine the relationship of PHH-associated CSF L1CAM and APP elevations to neurodevelopment outcomes at 18-24 months corrected age. The candidate proposes to leverage his participation in the Hydrocephalus Clinical Research Network to establish a multi- institutional neonatal CSF repository at Washington University. CSF levels of L1CAM and APP in PHH will be measured using ELISAs and compared with those in intraventricular hemorrhage and other neurological conditions common to preterm infants. The association between these CSF proteins and ultrasound-based measures of ventricular size will defined, and the relative gains afforded by CSF L1CAM and APP in identifying infants that require VP shunts will be estimated. Finally, the relationship between CSF L1CAM and APP levels and neurodevelopment outcome will be determined using Bayley Scales of Infant Development-III scoring at 18-24 months corrected age. If successful, these studies will advance the field of PHH by providing crucial data for the development of CSF L1CAM and APP levels as markers of PHH-associated neurological disability. The most immediate benefit of these markers would be to complement existing image-based ventricular measures to better inform clinical trials directed at improving the outcomes of infants with PHH. PUBLIC HEALTH RELEVANCE: Post-hemorrhagic hydrocephalus (PHH) of prematurity is the most frequent cause of severe cognitive and motor disability in preterm infants. Despite its profound effects on neurological outcome, there has been relatively little research into optimizing the treatment of this condition. This project investigates new protein markers intended to provide physicians with important feedback in real time about the effectiveness of treatment in preventing long-term neurological disability.