New Paradigms of Cerebral Palsy Etiology: A Comprehensive Case Control Study

该提案是CP 5年病例对照研究R01申请的修订版本（New paradigm of CP病因学1R01NS055101）。我们现在建议进行一项为期两年的病例对照研究，集中关注一个丰富的暴露信息来源，即新生儿血斑，该研究可用于1986年以来所有心肌梗死新生儿，并辅以孕妇关于妊娠暴露的访谈、出生证明数据、新生儿甲状腺激素筛查数据，以及（如果有的话）孕妇血清检测。我们将收集和储存（但不分析）来自入组受试者及其父母的基于唾液的遗传物质。该项目的总体目标是评估患有CP的儿童与匹配对照的儿童在与炎症、缺氧、凝血和甲状腺激素产生相关的新生儿基因表达以及出生时血液中病毒的存在方面的差异程度。通过与密歇根大学（University of Michigan）和德沃斯儿童医院（DeVos Children’s Hospital）的合作，我们将把招生范围从密歇根州中部扩大到密歇根州西部和东南部，在两年内招收440名病例和对照组患者，这与我们最初计划的5年时间相同。血斑材料将在三个实验室进行评估：mRNA表达将在Van Andel研究所（Grand Rapids， MI）进行三份评估；关键mRNA种类将在MSU进行qPCR进一步评估；病毒基因组标记将在明尼苏达大学进行检测。产妇产前标本将在密歇根州立大学进行评估。我们将扩展这些假设，以包括母亲在怀孕期间暴露在母体血清中可以检索的部分受试者。通过将分子信息与自我报告和记录的临床事件和情况联系起来，产妇访谈和出生证明将为上述分析提供信息。

This proposal is a revised version of an R01 application for a comprehensive five-year case-control study of CP (New Paradigms of CP Etiology 1R01NS055101). We now propose to perform a two year case-control study that focuses centrally on one rich source of exposure information, the newborn blood spot, which is available on all MI births since 1986, supplemented with a maternal interview about pregnancy exposures, birth certificate data, newborn thyroid hormone screening data, and, when available, maternal serum assays. We will collect and store (but not assay) salivary-based genetic material from enrolled subjects and their parents. The overall aim of the project is to assess the extent to which children with CP and matched controls differ in newborn expression of genes relating to inflammation, hypoxia, coagulation and thyroid hormone production, as well as presence of viruses in blood at birth. Through collaborations with the University of Michigan and the DeVos Children’s Hospital, we will expand our enrollment from Central Michigan to West and Southeast Michigan, enrolling the same number of cases and controls (440) in two years as we had originally planned in five years. The blood spot material will be assessed in three laboratories: mRNA expression will be assessed in triplicate at the Van Andel Research Institute (Grand Rapids, MI); key mRNA species will be further assessed by qPCR at MSU; viral genomic markers will be examined at the University of Minnesota. Maternal antenatal specimens will be assessed at MSU. We will extend these hypotheses to include maternal exposures in pregnancy in the fraction of subjects for whom maternal serum can be retrieved. Maternal interviews and birth certificates will inform the above analyses by linking molecular information to self-reported and recorded clinical events and conditions. 