Prenatal Extracellular Vesicles and Steroid Hormones as Biological Mechanisms Underlying Gestational Factors Associated with Neurodevelopmental Risk

项目摘要/摘要 申请者的职业目标是领导一个多学科的研究项目，该项目将调查 围产期母体、胎儿和胎盘生理影响胎儿大脑发育的途径 以及神经发育障碍的风险，包括自闭症谱系障碍(ASD)。这项研究将 实施翻译和临床研究方法，以发现可能 作为早期识别高危儿童的工具。为了有效地建立和领导这一研究计划， 在纵向研究设计、分子生物学、内分泌学、临床心理学/精神病学、 而且统计数据是必需的。K99研究旨在通过评估独立和 孕期母胎EVS与母胎类固醇激素作为潜在生物学效应的相互作用 婴儿神经行为和社会情绪发育的潜在机制。出生后，升高的EV- 相关蛋白(EV-AP)水平和EV microRNAs(MiRNAs)上调已在 患有包括自闭症在内的神经精神疾病的个人。然而，之前没有任何研究评估过 产前母儿EV-AP水平与儿童晚期神经发育的关系它也一直是 研究表明，较高水平的Δ4类固醇激素(孕酮，17α-羟基孕酮， 羊水中的雄激素(雄烯二酮和睾酮)与更严重的自闭症相关行为有关。 因此，EVS和类固醇激素的异常水平与ASD的病理生理学有关。 拟议的K99研究将使用生物学数据(孕妇/胎儿EVS、孕妇/胎儿类固醇激素)和数据 通过神经发育评估获得，这是一项大型纵向妊娠队列研究的一部分 确定EV-AP水平升高和Δ-4类固醇水平升高对婴儿的交互影响 神经行为和社会情绪发展。EV-AP和Δ4类固醇激素水平升高 在诊断为妊娠期高血压疾病或妊娠期糖尿病的女性中也观察到了这种情况 糖尿病，这种情况与后代神经发育风险增加有关，这表明 这些生物学机制可能调节与这些妊娠相关的神经发育风险。 条件。R00研究将涉及一项温和的调解分析，以评估EV-AP水平是否 而Δ4类固醇有助于观察到高血压疾病与 妊娠/妊娠期糖尿病与后代神经行为和社会情绪发育。这 该方法将阐明神经行为发育的新生物学机制，并可能提供 这是确定需要早期干预服务的儿童的重要工具。

Project Summary/Abstract The applicant's career goal is to lead a multidisciplinary research program that will investigate a network of perinatal pathways through which maternal, fetal, and placental physiology impacts fetal brain development and risk for neurodevelopmental disorders, including autism spectrum disorder (ASD). The research will implement translational and clinical research approaches to uncover early-emerging biomarkers that may serve as tools for early identification of at-risk children. To effectively establish and lead this research program, intensive training in longitudinal study design, molecular biology, endocrinology, clinical psychology/psychiatry, and statistics is required. The K99 study aims to address a crucial gap by evaluating the independent and interactive effects of prenatal maternal/fetal EVs and maternal/fetal steroid hormones as potential biological mechanisms underlying infant neurobehavioral and social-emotional development. Postnatally, elevated EV- associated protein (EV-AP) levels and upregulation of EV microRNAs (miRNAs) have been observed in individuals with neuropsychiatric conditions including ASD. However, no prior studies have evaluated the relationship between prenatal maternal/fetal EV-AP levels and later child neurodevelopment. It has also been shown that higher levels of the Δ4 steroid hormones (progesterone, 17α-hydroxy-progesterone, androstenedione and testosterone) in amniotic fluid are associated with greater ASD-related behaviors. Therefore, aberrant levels of both EVs and steroid hormones have been implicated in ASD pathophysiology. The proposed K99 study will use biological data (maternal/fetal EVs, maternal/fetal steroid hormones) and data obtained through neurodevelopmental assessments as part of a large, longitudinal pregnancy cohort study to determine the interactive effect of elevated EV-AP levels and elevated levels of the Δ4 steroids on infant neurobehavioral and social-emotional development. Elevated levels of EV-AP and Δ4 steroid hormones have also been observed in women diagnosed with a hypertensive disorder of pregnancy or gestational diabetes mellitus, conditions that are associated with increased neurodevelopmental risk in offspring, suggesting that these biological mechanisms may mediate the neurodevelopment risk associated with these gestational conditions. The R00 study will involve a moderated mediation analysis to evaluate whether the level of EV-APs and Δ4 steroids contributes to the observed association between hypertensive disorders of pregnancy/gestational diabetes mellitus and offspring neurobehavioral and social-emotional development. This approach will elucidate new biological mechanisms underlying neurobehavioral development and may provide important tools to identify children in need of early intervention services.