Research Project: Pathologic Significance of Maternal Autoantibodies

研究项目：母体自身抗体的病理意义

• 批准号: 10430108
• 负责人: JUDY A. VAN DE WATER
• 金额: $ 20.8万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-21 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10430108
• 关键词: Address; Adjustment Disorders; Affect; Age; Anatomy; Animals; Antibodies; Antigens; Area; Autoantibodies; Autoantigens; Behavior; Behavioral; Bioinformatics; Biological; Biological Markers; Biological Models; Biometry; Brain; Child; Clinical; Clinical Research; Cognitive; Complex; Data; Development; Developmental Gene; Diagnosis; Early identification; Embryo; Environment; Epitopes; Exhibits; Experimental Models; Exposure to; Fetus; Foundations; Funding; Future; Gene Expression; Glial Fibrillary Acidic Protein; High-Risk Pregnancy; Human; Immune; Immunohistochemistry; Impairment; Individual; Institutes; Intellectual and Developmental Disabilities Research Centers; Intellectual functioning disability; Intervention; Label; Lead; Link; Measures; Modeling; Molecular; Molecular Analysis; Mothers; Mus; Neuroanatomy; Neurodevelopmental Disorder; Outcome; Outcome Measure; PIK3CG gene; Pathogenicity; Pathologic; Pathology; Pathway interactions; Pattern; Phenotype; Pilot Projects; Placenta; Population; Positioning Attribute; Pre-Clinical Model; Pregnancy; Prevention strategy; Proteins; Rattus; Research; Research Design; Research Project Grants; Research Project Summaries; Risk; Risk Factors; Rodent; Sampling; Sensitivity and Specificity; Signal Transduction; Social Behavior; Specificity; Testing; Therapeutic Intervention; Time; Transcript; United States; associated symptom; autism spectrum disorder; autistic children; base; biomarker development; cell type; clinically relevant; cohort; differential expression; disorder risk; epidemiology study; experience; fetal; frontal lobe; high reward; high risk; improved; individualized medicine; mouse model; neurodevelopment; next generation; nonhuman primate; notch protein; novel therapeutic intervention; offspring; pathogenic autoantibodies; postnatal; pre-clinical; preclinical study; prenatal; prenatal exposure; prevent; prospective; repetitive behavior; single-cell RNA sequencing; social; targeted treatment; transcriptome sequencing; transcriptomics; treatment research

PROJECT SUMMARY – RESEARCH PROJECT: PATHOLOGIC SIGNIFICANCE OF MATERNAL AUTOANTIBODIES Autism spectrum disorder (ASD) affects about 1 in 59 children in the United States, yet there remains relatively little understanding of underlying cause(s) and few options for therapeutic interventions. Our research team is evaluating an immune-based mechanism implicated in ASD – prenatal exposure to maternal autoantibodies that target proteins in the developing fetal brain. A significant subset of mothers who have a child with ASD produce antibodies to fetal brain proteins that are critical for neurodevelopment. We hypothesize that these antibodies cross the placenta during gestation, interact with fetal brain protein targets, alter neurodevelopment, and lead to a maternal autoantibody (AB) related (MAR) form of ASD. We have found that up to 26% of cases are associated with MAR. Previous preclinical studies have used mice and nonhuman primates to evaluate the pathogenic importance of MAR exposure. In these model systems, offspring born to dams periodically injected with MAR AB during gestation exhibit atypical neurodevelopment and behavior. While these passive transfer models provide support for MAR as a risk factor for ASD, they do not reflect the constant exposure that occurs throughout gestation experienced by the human fetus. Our research team has recently validated a highly accurate test for MAR AB, and established the next generation of more sophisticated antigen-driven models, which together will allow us to evaluate the pathogenic significance of continuous exposure to specific combinations of MAR AB. We are now positioned to utilize the sophisticated social and cognitive processing capabilities and complex neuroanatomy of the rat model system to evaluate the pathogenic significance of prenatal MAR exposure. Here we propose an exploratory, discovery-based, research project that will utilize multiple MIND Institute IDDRC Cores to test the hypothesis that continuous gestational exposure to specific combinations of MAR AB is causally linked to changes in brain and behavioral development of the offspring. Through human clinical studies, we will first determine the association between the MAR ASD AB patterns and neurodevelopmental profiles among the children with ASD from human samples collected prospectively during pregnancy from high-risk mothers (Aim 1). We will then leverage these clinically relevant data to directly assess the pathologic significance of prenatal exposure to epitope-specific AB in generating ASD-relevant behaviors in the antigen-driven rat model (Aim 2). Data derived from Aim 2 will indicate which of the individual ABs are pathologically significant, and which are biomarkers of risk with no pathologic relevance. In this model, the embryos will be continuously exposed to the MAR ABs throughout gestation, thereby better representing the human MAR ASD environment and providing an experimental model system to determine downstream molecular pathways (Aim 3). This high-risk, potentially high-reward, proposal is an essential next step in developing novel therapeutics and strategies for prevention.

项目摘要 - 研究项目：孕产妇的病理意义 自动抗体 自闭症谱系障碍（ASD）在美国影响59名儿童中约1个，但仍然相对仍然 对基本原因的了解很少，治疗干预措施的选择很少。我们的研究团队是 评估在ASD中实施的基于免疫的机制 - 产前暴露于母体自身抗体 靶向发育中的胎儿大脑中的蛋白质。有一个有ASD农产品的孩子的母亲的大部分子集 对神经发育至关重要的胎儿脑蛋白的抗体。我们假设这些抗体 妊娠期间越过plapeta，与胎儿脑蛋白靶标相互作用，改变神经发育并导致 ASD相关的母体自身抗体（AB）形式。我们发现多达26％的案件是相关的 与三月。以前的临床前研究使用小鼠和非人类隐私来评估病原体 MAR暴露的重要性。在这些模型系统中，大坝出生的后代定期注射了Mar 妊娠期间的AB展示非典型神经发育和行为。而这些被动转移模型 为MAR作为ASD的危险因素提供支持，它们不能反映出整个过程的持续暴露 人类胎儿经历的妊娠。我们的研究团队最近验证了高度准确的测试 Mar AB，并建立了下一代更复杂的抗原驱动模型，该模型将共同 允许我们评估连续暴露于MAR AB的特定组合的致病意义。 我们现在可以利用复杂的社会和认知处理能力以及复杂的 大鼠模型系统的神经解剖学评估产前MAR暴露的致病意义。这里 我们提出了一个探索性，基于发现的研究项目，该项目将利用多个思维研究所IDDRC 核心测试以下假设，即连续妊娠暴露于MAR AB的特定组合是有因由 与大脑的变化和后代的行为发展有关。通过人类的临床研究，我们将 首先确定MAR ASD AB模式与神经发育概况之间的关联 高危母亲怀孕期间预期收集的人类样本ASD的儿童（AIM 1）。然后，我们将利用这些临床相关数据直接评估产前的病理意义 在抗原驱动的大鼠模型中产生与ASD相关的行为时，暴露于表位特异性AB（AIM 2）。 AIM 2得出的数据将表明哪些个体ABS具有病理意义，哪些是 没有病理意义的风险生物标志物。在此模型中，胚胎将不断暴露于 整个妊娠期，Mar腹肌，从而更好地代表人类ASD环境并提供 一个实验模型系统，以确定下游分子途径（AIM 3）。这种高风险，有可能 高级，提案是开发新型治疗和预防策略的重要下一步。