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Research Project: Pathologic Significance of Maternal Autoantibodies

研究项目：母体自身抗体的病理意义

基本信息

批准号：
10220103
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
项目类别：
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/10220103
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

项目摘要

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.

项目总结-研究项目：孕产妇死亡的病理学意义自身抗体自闭症谱系障碍（ASD）影响美国59名儿童中的1名，但仍有相对对根本原因了解甚少，治疗干预的选择很少。我们的研究团队是评估与ASD有关的免疫机制-产前暴露于母体自身抗体，发育中的胎儿大脑中的靶蛋白。一个重要的子集的母亲谁有一个孩子与ASD生产胎儿脑蛋白的抗体对神经发育至关重要。我们假设这些抗体在妊娠期间穿过胎盘，与胎儿脑蛋白靶点相互作用，改变神经发育，并导致 ASD的母体自身抗体（AB）相关（MAR）形式。我们发现高达26%的病例与以前的临床前研究使用小鼠和非人灵长类动物来评估致病性暴露的重要性。在这些模型系统中，定期注射MAR的母鼠所生的后代妊娠期AB表现出非典型的神经发育和行为。虽然这些被动转移模型虽然它们为MAR作为ASD的风险因素提供了支持，但它们并不反映整个过程中发生的持续暴露，人类胎儿所经历的怀孕。我们的研究团队最近验证了一种高度准确的测试， MAR AB，并建立了下一代更复杂的抗原驱动模型，这些模型将共同使我们能够评估持续暴露于特定MAR AB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，大鼠模型系统的神经解剖学，以评估产前MAR暴露的致病意义。这里我们提出了一个探索性的、基于发现的研究项目，该项目将利用多个MIND研究所的IDDRC 用于检验以下假设的核心：妊娠期持续暴露于MAR AB的特定组合与与后代大脑和行为发育的变化有关。通过人类临床研究，我们将首先确定MAR ASD AB模式和神经发育概况之间的关联，在妊娠期从高危母亲中前瞻性收集人类样本， 1）。然后，我们将利用这些临床相关数据，直接评估产前诊断的病理意义。暴露于表位特异性AB在抗原驱动的大鼠模型中产生ASD相关行为（目的2）。从目标2中获得的数据将表明哪些单个AB具有病理学意义，哪些具有病理学意义。与病理学无关的风险生物标志物。在这个模型中，胚胎将持续暴露在在整个妊娠期间的MAR AB，从而更好地代表人类MAR ASD环境，并提供用于确定下游分子途径的实验模型系统（目标3）。这种高风险的，潜在的高回报的建议是开发新疗法和预防策略的重要下一步。