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

本提案是一项为期5年的CP综合病例对照研究（CP病因学新范式1 R 01 NS 055101）的R 01申请的修订版。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，自1986年以来，所有MI出生均可获得该信息，并辅以有关妊娠暴露的母亲访谈、出生证明数据、新生儿甲状腺激素筛查数据以及（如可用）母亲血清测定。我们将从入组的受试者及其父母中收集并储存（但不分析）基于唾液的遗传物质。该项目的总体目标是评估患有CP的儿童和匹配的对照组在新生儿表达与炎症，缺氧，凝血和甲状腺激素产生有关的基因以及出生时血液中病毒存在的差异程度。通过与密歇根大学和DeVos儿童医院的合作，我们将扩大我们的招生从密歇根州中部到密歇根州西部和东南部，在两年内招收相同数量的病例和对照（440），因为我们最初计划在五年内。将在三个实验室评估血斑材料：将在货车Andel研究所（大急流城，MI）一式三份评估mRNA表达;将在MSU通过qPCR进一步评估关键mRNA物质;将在明尼苏达大学检查病毒基因组标志物。将在MSU评估母体产前标本。我们将扩展这些假设，以包括妊娠期母体暴露在母体血清中的受试者比例。母亲访谈和出生证明将通过将分子信息与自我报告和记录的临床事件和状况联系起来，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. 