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

出血后脑积水脑脊液中 L1CAM 和淀粉样前体蛋白的水平

• 批准号: 8300378
• 负责人: David Delmar Limbrick
• 金额: $ 15.87万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300378
• 关键词: Affect; Aftercare; Age; Amyloid beta-Protein Precursor; Atrophic; Biology; Cannulations; Caring; Cephalic; Cerebral Palsy; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Childhood; Clinical Research; Clinical Treatment; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Complement; Complication; Consensus; Creation of ventriculo-peritoneal shunt; Data; Development; Devices; Feedback; Hydrocephalus; Image; Implant; Individual; Infant; Infant Development; Injury; Interdisciplinary Study; K-Series Research Career Programs; Laboratories; Language; Measurement; Measures; Medicine; Mentors; Motor; Neonatal; Nerve Degeneration; Nervous System Trauma; Neural Cell Adhesion Molecule L1; Neurites; Neurologic; Neurological outcome; Neurosurgeon; Newborn Infant; Outcome; Pathogenesis; Pediatric Hospitals; Physicians; Play; Population; Premature Birth; Premature Infant; Process; Proteins; Proteomics; Recruitment Activity; Regression Analysis; Regulation; Relative (related person); Research; Research Methodology; Research Training; Role; Sampling; Scientist; Seizures; Spinal Puncture; Time; Training; Treatment Effectiveness; Ultrasonography; United States National Institutes of Health; Universities; Variant; Ventricular; Very Low Birth Weight Infant; Washington; base; career development; cohort; disability; implantation; improved; infant outcome; interest; intraventricular hemorrhage; nervous system disorder; neurodevelopment; novel marker; premature; prevent; programs; repository; skills training; synaptogenesis; tool; white matter

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.

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，特别致力于推进早产儿出血后脑积水 (PHH) 领域的发展，并改善患有这种疾病的婴儿的护理和结果。该提案中概述的严格职业发展计划既有教学内容，也有在博士实验室进行的指导性科学培训。华盛顿大学的特里·因德和大卫·霍尔兹曼。拟议的项目建立在该大学由 NIH 支持的跨学科研究中心和临床研究培训中心的优势之上，重点对候选人进行临床研究方法、脑脊液 (CSF) 蛋白质生物学以及早产儿神经发育和残疾方面的培训。通过此 CDA 获得的额外培训和技能将补充候选人之前的研究背景，并提供成为独立临床医生科学家所需的新专业知识。 该提案的中心假设是，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 中选择性增加，并且这些蛋白的持续升高与心室大小、脑室腹膜 (VP) 分流需求的增加以及不良的神经学结果。该提案的具体目标是： 1) 比较对照、PHH 和其他神经系统疾病中 CSF L1CAM 和 APP 的水平； 2) 定义 PHH 中 CSF L1CAM 和 APP 与心室大小之间的关联； 3) 确定 PHH 相关的 CSF L1CAM 和 APP 升高与 18-24 个月校正年龄时神经发育结果的关系。候选人提议利用他对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。将使用 ELISA 测量 PHH 中 CSF 的 L1CAM 和 APP 水平，并与脑室内出血和早产儿常见的其他神经系统疾病中的水平进行比较。将定义这些 CSF 蛋白与基于超声的心室大小测量之间的关联，并估计 CSF L1CAM 和 APP 在识别需要 VP 分流的婴儿方面提供的相对增益。最后，CSF L1CAM 和 APP 水平与神经发育结果之间的关系将使用 18-24 个月校正年龄的贝利婴儿发育量表 III 评分来确定。如果成功，这些研究将为 CSF L1CAM 和 APP 水平的发展（作为 PHH 相关神经功能障碍的标志物）提供重要数据，从而推动 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，更好地为旨在改善 PHH 婴儿预后的临床试验提供信息。 公共卫生相关性：早产儿出血后脑积水 (PHH) 是早产儿严重认知和运动障碍的最常见原因。尽管它对神经系统结果产生深远影响，但优化这种疾病治疗的研究相对较少。该项目研究新的蛋白质标记物，旨在为医生提供有关治疗预防长期神经残疾的有效性的实时重要反馈。