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Placental Transcriptomics and Risk for Schizophrenia

胎盘转录组学和精神分裂症的风险

基本信息

批准号：
10321945
负责人：
Gianluca Ursini
金额：
$ 18.1万
依托单位：
LIEBER INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-24 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321945
关键词：
Accounting Affect Animals Area Behavior Biological Markers Biological Process Birth Blood Brain Diseases Child Data Detection Development Discipline of obstetrics Disease Epidemiology Exposure to Female Gene Expression Genes Genetic Genetic Markers Genetic Risk Genetic Variation Genome Genomics Genotype Goals Human Hydrocortisone Immune response Individual Infant Inflammation Lead Life Link Measures Mediating Mediator of activation protein Methodology Molecular Morbidity - disease rate Nature Neonatal Newborn Infant Outcome Pathway Analysis Pathway interactions Perinatal Physiology Placenta Placental Biology Placentation Pre-Clinical Model Predisposition Pregnancy Pregnancy Complications Pregnancy Outcome Premature Birth Prevention Prevention strategy Process Protein Isoforms Proteins Questionnaires RNA Splicing Relative Risks Research Risk Risk Factors Role Salivary Sampling Schizophrenia Stress Testing Transcript Translating Weight Work base case control cell type cohort disorder risk epidemiology study fetal genetic risk factor genomic predictors high risk innovation insight male maternal stress neurobehavior neurodevelopment neurodevelopmental effect novel novel strategies offspring perinatal complications polygenic risk score postnatal precision medicine prenatal preservation prevent risk variant schizophrenia risk sex tool transcriptome transcriptome sequencing transcriptomics

项目摘要

Our main objective is to find the factors mediating the relationship between genetic risk factors, complications in early life (ELCs, i.e. pre-, and perinatal) and altered neuro- development (ND) in humans, so that, in high-risk individuals, disorders of ND such as schizophrenia (SZ), can be prevented or rescued in early stages. Epidemiological findings show that ELCs increase the risk for ND disorders including SZ; preclinical models show that ELCs alter ND, an effect partially mediated by gene expression in placenta, with males more vulnerable than females. However, the mechanism linking ELCs with SZ are still elusive. Our recent human work found that genetic factors converge with placenta biology in affecting risk for SZ. Here, we focus on detecting the molecular mediators involved: that is, the molecules that, by regulating placenta's physiology, regulate ND, drive susceptibility to SZ, and may mediate the interaction between genetic factors and ELCs on the risk for the disorder. We propose a multi-step strategy, which leverages our strengths in analyzing transcriptomic and genetic data, using well-established and innovative methodologies to explore a novel area of research: the relationship between genomic risk factors, placenta and SZ. We will first investigate the transcriptomic correlates of genetic risk factors for SZ in the placenta, and we will analyze whether gene isoforms associated with risk for SZ are co-expressed in placenta, as part of specific biological processes. Using genotype-based prediction of gene expression in large cohorts, we will identify the specific placental isoforms associated with SZ case-control status. We will then generate placental genomic predictors of SZ risk, and we will test their relationship with ND outcomes. To investigate sex-specific placental processes relevant for SZ, we will stratify each analysis by sex. We expect our data to converge in identifying placental molecules and pathways that are relevant for SZ. The detection of such molecules may be translated into the development of novel prenatal prevention of SZ, aimed at preserving / optimizing the important placental support to ND, and the development of novel postnatal prevention, based on the identification of high-risk individuals – through placental and genetic biomarkers.

我们的主要目标是找到调节遗传风险之间关系的因素早期生命中的因素、并发症(ELCs，即产前和围产期)和神经改变- 人类的发育(ND)，因此，在高危个体中，ND的障碍，如精神分裂症(SZ)，可以在早期预防或挽救。流行病学调查结果显示ELC增加了包括SZ在内的ND疾病的风险；临床前模型显示在男性中，ELCs改变ND，这一效应部分由胎盘中基因表达介导比雌性更脆弱。然而，将ELCS与深圳联系起来的机制仍然是难以捉摸。我们最近的人类研究发现，遗传因素与胎盘生物学汇聚在一起影响深圳的风险。在这里，我们专注于检测涉及的分子介体：是一种分子，通过调节胎盘的生理，调节ND，驱动易感性可能在遗传因素与ELCs之间的交互作用中起到中介作用。这是一种混乱。我们提出了一个多步骤的策略，利用我们在分析转录和基因数据，使用成熟和创新的方法探索一个新的研究领域：基因组危险因素与胎盘之间的关系和SZ.我们将首先研究SZ遗传风险因素的转录相关我们将分析与SZ风险相关的基因亚型是否在胎盘中共表达，作为特定生物学过程的一部分。使用基于基因的预测大队列中的基因表达，我们将确定特定的胎盘与深圳病例对照状态相关的异构体。然后我们将产生胎盘基因组 SZ风险的预测因素，我们将测试它们与ND结果的关系。去调查与SZ相关的性别特定的胎盘过程，我们将按性别对每个分析进行分层。我们期待我们的数据在识别胎盘分子和途径方面收敛与深圳相关。这种分子的检测可以转化为显影 SZ的新型产前预防，旨在保存/优化重要的胎盘支持新城疫，并开发新的产后预防，基于通过胎盘和遗传生物标记物识别高危个体。