Cellular, molecular, and functional imaging approaches to understanding early neurodevelopment in autism

了解自闭症早期神经发育的细胞、分子和功能成像方法

• 批准号: 9560923
• 负责人: KATARZYNA CHAWARSKA
• 金额: $ 240.55万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-07 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9560923
• 关键词: 12 year old; Address; Affect; Age; Anatomy; Attention; Autistic Disorder; Behavior; Behavioral; Biological; Biological Markers; Biological Models; Biological Neural Networks; Birth; Brain; Brain imaging; Cells; Characteristics; Child; Childhood; Data; Development; Diagnosis; Diagnostic; Disease; Evaluation; Female; Fetal Development; Functional Imaging; Functional Magnetic Resonance Imaging; Genetic; Image; Impairment; Infant; Intellectual functioning disability; Interdisciplinary Study; Intervention; Investigation; Learning; Life; Link; Measures; Methodology; Methods; Molecular; Neonatal; Neurobiology; Neurology; Neuronal Plasticity; Neurons; Neurosciences; Newborn Infant; Organizational Change; Organoids; Patients; Pattern; Perinatal; Photons; Play; Pregnancy; Prognostic Marker; Prospective cohort; Psychopathology; Radiology Specialty; Reporting; Research Project Grants; Resolution; Risk; Risk Factors; Role; School-Age Population; Scientist; Second Pregnancy Trimester; Severities; Sex Characteristics; Siblings; Social Values; Stem cells; Symptoms; Synapses; System; Testing; Third Pregnancy Trimester; Time; Toddler; Training; base; behavioral study; cellular imaging; cohort; connectome; density; diagnostic biomarker; disorder risk; efficacy testing; executive function; fetal; high risk; human model; imaging approach; induced pluripotent stem cell; infancy; inhibitory neuron; innovation; male; molecular imaging; multidisciplinary; neonatal period; neural model; neurodevelopment; neuroimaging; neuromechanism; neurophysiology; novel; novel diagnostics; outcome prediction; predicting response; predictive modeling; prenatal; prognostic; programs; protective factors; recruit; relating to nervous system; resilience; response; risk sharing; sex; statistics

The Yale Center represents a multidisciplinary research program consisting of five inter-related research projects and four cores dedicated to advancing understanding of early neurobiology of ASD. The proposal brings together a team of experts from the fields of developmental psychopathology and neurobiology, genetics, neurology, radiology, neuroscience, and statistics to identify the molecular, cellular, and neural mechanisms related to ASD from prenatal stages to childhood. We focus our investigation on two cohorts of younger siblings of children with ASD who, due to familial factors, are at high risk (HR) for developing the disorder: a prospective cohort recruited pre- and perinatally and followed through 24 months, and a cohort of HR siblings who was well-characterized at 24 months through our past studies and will reach the age of 12 years during the life of the Yale ACE. These cohorts enable our search for neural signatures of ASD during fetal, neonatal, and school-age periods, as well as to examine the connectome across the spectrum of risk for ASD both in males and females. Although neural and behavioral markers of ASD have been reported in 6- month-old infants later diagnosed with ASD, to our best knowledge, this is the first investigation into both fetal and neonatal functional connectivity in ASD. Emerging data suggest that male, but not female, ASD subjects demonstrate significant alterations in neural networks, and – for the first time – the proposed studies will identify not only the changes in connectivity in ASD but also the impact of fetal/neonatal sex upon these changes. Since recent studies demonstrate neuroplasticity in the developing brain across the late second and third trimesters of gestation, it is essential to understand if the factors associated with ASD are developing in this same time frame and to understand any sex differences that may be apparent even at that early age. The iPSC derived organoid system models human fetal development, allowing us to investigate neurobiological risk and protective factors that play a unique role in this period and may enable the discovery of patient-specific neuronal or stem cell biomarkers that could be used as predictors of risk or resilience in ASD. The Yale ACE aims rely on application of cutting-edge approaches to the analysis the connectome, fetal and neonatal imaging modeling neural development using the iPSC methodology with high resolution dual photon imaging approaches, the development of early markers for ASD, studying early attention and learning, novel predictive models relating brain organization to behavior, and statistical approaches for integrating the spectrum of data types across to address these aims. Results from the combined projects have a great potential to identify novel diagnostic and prognostic markers at the time of birth, identify neural, cellular, and molecular bases of risk and protective mechanisms in ASD, and clarify neural bases of sex differences in ASD.

耶鲁中心代表了一个多学科研究项目，由五项相互关联的研究组成 项目和四个核心致力于增进对自闭症谱系障碍早期神经生物学的理解。提案 汇集了来自发展精神病理学和神经生物学领域的专家团队， 遗传学、神经学、放射学、神经科学和统计学来识别分子、细胞和神经 从产前阶段到儿童期与 ASD 相关的机制。我们的调查重点是两个群体 患有自闭症谱系障碍 (ASD) 儿童的弟弟妹妹，由于家庭因素，他们有患上自闭症谱系障碍 (ASD) 的高风险 (HR) 障碍：在产前和围产期招募并随访 24 个月的前瞻性队列，以及 根据我们过去的研究，HR 兄弟姐妹在 24 个月大时就已经表现良好，并将年满 12 岁 在耶鲁大学 ACE 的一生中。这些队列使我们能够在 胎儿、新生儿和学龄期，以及检查跨风险范围的连接组 自闭症谱系障碍（ASD）在男性和女性中均有发生。尽管 ASD 的神经和行为标记已在 6- 一个月大的婴儿后来被诊断出患有自闭症谱系障碍，据我们所知，这是对胎儿和婴儿的首次调查 和自闭症谱系障碍 (ASD) 中的新生儿功能连接。新数据表明，自闭症谱系障碍对象是男性，而非女性 展示了神经网络的重大改变，并且首次提出的研究将 不仅确定自闭症谱系障碍连通性的变化，还确定胎儿/新生儿性别对这些变化的影响 变化。由于最近的研究表明，发育中的大脑在第二和第二阶段具有神经可塑性 在妊娠晚期，有必要了解与自闭症谱系障碍 (ASD) 相关的因素是否正在发生 在同一时间范围内，了解即使在很小的时候也可能出现的任何性别差异。这 iPSC 衍生的类器官系统模拟人类胎儿发育，使我们能够研究神经生物学风险 和保护因素在这一时期发挥独特的作用，可能有助于发现患者特异性的 神经元或干细胞生物标志物可用作 ASD 风险或恢复力的预测因子。耶鲁王牌 目标依赖于应用尖端方法来分析胎儿和新生儿的连接组 使用 iPSC 方法和高分辨率双光子成像对神经发育进行成像建模 方法、自闭症谱系障碍 (ASD) 早期标记的开发、研究早期注意力和学习、新颖的预测 将大脑组织与行为相关的模型，以及整合数据范围的统计方法 打字来实现这些目标。联合项目的结果具有识别新颖的潜力的巨大潜力 出生时的诊断和预后标记，识别风险和风险的神经、细胞和分子基础 自闭症谱系障碍的保护机制，并阐明自闭症谱系障碍性别差异的神经基础。