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

描述（由申请人提供）：该职业发展奖（CDA）的候选人是一名儿科神经外科医生，对推进早产儿出血后脑积水（PHH）领域和改善患有这种疾病的婴儿的护理和结局特别感兴趣。该提案中概述的严格的职业发展计划既有教学组成部分，也有在华盛顿大学泰瑞·英德博士和大卫·霍尔茨曼博士实验室进行的指导性科学培训。拟议的计划建立在大学的NIH支持的跨学科研究中心和临床研究培训中心的优势，重点是候选人的临床研究方法，脑脊液（CSF）蛋白生物学，神经发育和早产儿残疾的培训。通过该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L1 CAM和淀粉样前体蛋白（APP）的水平选择性增加PHH，这些蛋白质的长期升高与脑室大小增加，脑室腹膜（VP）分流的要求，和不良的神经学结果。本提案的具体目的是：1）比较对照、PHH和其他神经系统疾病中CSF L1 CAM和APP的水平; 2）确定PHH中CSF L1 CAM和APP与脑室大小之间的相关性; 3）确定PHH相关CSF L1 CAM和APP升高与18-24个月矫正年龄时神经发育结局的关系。候选人提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的新生儿CSF储存库。将使用ELISA法测量PHH患者CSF中L1 CAM和APP的水平，并与脑室内出血和早产儿常见的其他神经系统疾病进行比较。将确定这些CSF蛋白与基于超声的心室大小测量之间的关联，并估计CSF L1 CAM和APP在识别需要VP分流的婴儿方面提供的相对增益。最后，将在18-24个月校正年龄时使用Bayley婴儿发育量表-III评分确定CSF L1 CAM和APP水平与神经发育结局之间的关系。如果成功，这些研究将通过为CSF L1 CAM和APP水平作为PHH相关神经功能障碍的标志物的发展提供关键数据来推进PHH领域。这些标记物最直接的好处是补充现有的基于图像的心室测量，以更好地为旨在改善PHH婴儿结局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.