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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：
10682407
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/10682407
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 Intellectual and Developmental Disabilities Research Centers Intellectual functioning disability Intervention Label 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 Symptoms Testing Therapeutic Intervention Time Transcript United States autism spectrum disorder autistic children biomarker development cell type clinical translation clinically relevant cohort comorbidity 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 strategies novel therapeutics 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：母体的病理学意义自身抗体在美国，大约每59名儿童中就有一名患有自闭症谱系障碍(ASD)，但相对来说对潜在原因缺乏了解(S)，几乎没有治疗干预的选择。我们的研究团队是评估自闭症孕妇产前暴露于母体自身抗体的基于免疫的机制发育中的胎儿大脑中的靶蛋白。孩子患有自闭症的母亲中有很大一部分会产生对神经发育至关重要的胎儿脑蛋白抗体。我们假设这些抗体在怀孕期间穿过胎盘，与胎儿大脑蛋白靶点相互作用，改变神经发育，并导致母体自身抗体(AB)相关(MAR)形式的ASD。我们发现，高达26%的病例与和Mar一起。以前的临床前研究已经使用小鼠和非人类灵长类动物来评估致病因素暴露于MAR的重要性。在这些模型系统中，定期注射MAR的母鸡所生的后代 AB在怀孕期间表现出不典型的神经发育和行为。虽然这些被动转移模型将MAR作为ASD的风险因素提供支持，它们并不反映在整个过程中发生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的MAR AB组合的致病意义。我们现在可以利用复杂的社交和认知处理能力和复杂性对大鼠模型系统进行神经解剖学研究，以评价产前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，该项目将利用多思维研究所IDDRC 核心来检验这样的假设，即妊娠期间持续接触特定的Mar AB组合是因果关系与后代大脑和行为发育的变化有关。通过人体临床研究，我们将首先确定MAR ASD AB模式与神经发育特征之间的关联从高危母亲孕期前瞻性采集的人类样本中获得的ASD儿童(目的 1)。然后，我们将利用这些临床相关数据来直接评估产前的病理意义。在抗原驱动的大鼠模型中暴露于表位特异性AB在产生ASD相关行为中的作用(目标2)。来自AIM 2的数据将表明哪些单个ABS具有病理意义，哪些是与病理无关的风险生物标记物。在这个模型中，胚胎将持续暴露在整个孕期的MAR ABS，从而更好地代表人类MAR ASD环境并提供确定下游分子途径的实验模型系统(目标3)。这种高风险、潜在的高回报的建议是开发新的治疗方法和预防策略的关键下一步。