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

产前细胞外囊泡和类固醇激素作为与神经发育风险相关的妊娠因素的生物机制

• 批准号: 10739066
• 负责人: Morgan Firestein
• 金额: $ 13.08万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739066
• 关键词: Address; Age Months; Amniotic Fluid; Androstenedione; Award; Basic Science; Biological; Biological Markers; Biometry; Brain; Cells; Child; Clinical Psychology; Clinical Research; Cohort Studies; Communication; Data; Development; Diagnosis; Disease; Early Intervention; Early identification; Emotional; Endocrinology; Enzyme-Linked Immunosorbent Assay; Functional disorder; Gene Expression Regulation; Gestational Diabetes; Goals; Health; Hydroxyprogesterone; Hypertension; Individual; Infant; Interdisciplinary Study; Lead; Lifestyle-related condition; Longitudinal Studies; Mammalian Cell; Mass Spectrum Analysis; Measurement; Measures; Mediating; Mediation; Metabolic; MicroRNAs; Molecular Biology; Motor; Neurodevelopmental Deficit; Neurodevelopmental Disorder; Outcome; Parents; Pathway interactions; Perinatal; Physiology; Plasma; Pregnancy; Pregnant Women; Progesterone; Proteins; Psychiatry; Quality of life; RNA; Reporting; Research; Research Design; Risk; Risk Factors; Role; Source; Steroid biosynthesis; Steroids; Testosterone; Toddler; Training; Transcriptional Regulation; Translational Research; Up-Regulation; Woman; autism spectrum disorder; career; cohort; design; epidemiology study; extracellular vesicles; fetal; fetal blood; longitudinal dataset; motor deficit; neurobehavioral; neurodevelopment; neuropsychiatry; offspring; postnatal; pregnancy disorder; prenatal; programs; recruit; service intervention; skills; social; statistics; steroid hormone; tool; translational research program

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.

项目概要/摘要 申请人的职业目标是领导一个多学科研究项目，该项目将调查一个网络 母体、胎儿和胎盘生理学影响胎儿大脑发育的围产期途径 以及神经发育障碍的风险，包括自闭症谱系障碍（ASD）。 实施转化和临床研究方法来发现早期出现的生物标志物 作为早期识别高危儿童的工具，以有效地建立和领导这项研究计划， 纵向研究设计、分子生物学、内分泌学、临床心理学/精神病学、 K99 研究旨在通过评估独立和统计数据来解决关键差距。 产前母体/胎儿 EV 和母体/胎儿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感发育的潜在机制，出生后，EV-升高。 相关蛋白 (EV-AP) 水平和 EV microRNA (miRNA) 的上调已在 然而，之前没有研究评估过患有神经精神疾病（包括自闭症谱系障碍）的人。 产前母亲/胎儿 EV-AP 水平与后期儿童神经发育之间的关系也已得到证实。 研究表明，较高水平的 Δ4 类固醇激素（黄体酮、17α-羟基黄体酮、 羊水中的雄烯二酮和睾酮）与更大的 ASD 相关行为有关。 因此，EV 和类固醇激素的异常水平与 ASD 病理生理学有关。 拟议的 K99 研究将使用生物学数据（母体/胎儿 EV、母体/胎儿类固醇激素）和数据 作为大型纵向妊娠队列研究的一部分，通过神经发育评估获得 确定 EV-AP 水平升高和 Δ4 类固醇水平升高对婴儿的交互作用 EV-AP 和 Δ4 类固醇激素水平升高。 在被诊断患有妊娠高血压疾病或妊娠糖尿病的女性中也观察到了这一现象 与后代神经发育风险增加相关的疾病，表明 这些生物学机制可能介导与这些妊娠相关的神经发育风险 R00 研究将涉及有调节的中介分析，以评估 EV-AP 的水平。 和 Δ4 类固醇有助于观察到的高血压疾病之间的关联 妊娠/妊娠糖尿病和后代神经行为和社会情感发育。 该方法将阐明神经行为发育背后的新生物学机制，并可能提供 识别需要早期干预服务的儿童的重要工具。