Cell-specific molecular mechanisms underlying brain pathology in ASD

ASD 脑病理学背后的细胞特异性分子机制

• 批准号: 9149339
• 负责人: Cynthia Schumann
• 金额: $ 15.7万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-24 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9149339
• 关键词: Address; Adult; Age; Age-Years; Archives; Auditory area; Autopsy; Biological Markers; Biological Response Modifier Therapy; Blood; Brain; Brain Pathology; Brain region; Cell Aging; Cell Count; Cell Death; Cell Size; Cells; Child; Childhood; Code; Cognitive; Development; Emotional; Gene Expression; Gene Expression Alteration; Gene Expression Profile; Genes; Goals; Growth; Health; Heterogeneity; Human; Image; Immune; Immune response; Individual; Intervention; Investigation; Knowledge; Lasers; Life; Link; Longevity; Magnetic Resonance Imaging; Measures; Messenger RNA; Microglia; Microscopy; Molecular; Molecular Profiling; Neurons; Outcome; Paint; Pathogenesis; Pathology; Pathway interactions; Pattern; Pilot Projects; Population; Proteins; RNA Sequences; Research; Sampling; Structure; Structure of superior temporal sulcus; Subgroup; Suspension substance; Suspensions; Target Populations; Techniques; Temporal Lobe; Testing; Translating; age related; autism spectrum disorder; biological research; brain cell; brain research; brain tissue; cell age; cell type; cellular development; cellular pathology; histological studies; mind control; neuronal cell body; novel; programs; regional difference; sex; social; transcriptome; transcriptome sequencing; transcriptomics

 DESCRIPTION (provided by applicant): Alterations in brain structure and function in most individuals with an autism spectrum disorder (ASD) begin early in life, however they continue to change during development and vary throughout lifespan. These age-related differences are region-specific and most evident in higher-order cognitive, social and emotional brain regions. Our longitudinal magnetic resonance imaging (MRI) studies suggest that, of the five lobes, temporal cortical growth in children with ASD deviates most substantially from typical development, beginning at 2 years of life. Although this phenomenon is most evident during childhood, we found that cellular alterations continue and change throughout lifespan. Neuron numbers are reduced in temporal cortical and subcortical regions in ASD adults and a subset of ASD brains has excessive microglial activation, suggesting an aberrant immune response in the brain. Whether these differences exist during childhood or are the result of degenerative cell loss remains a mystery. It is clear though that structural and cellular alterations found in ASD brain vary by region and age, and are cell-specific. The heterogeneity and changing pathology of the ASD brain presents complications for translating biological research to the development of biotheraputics to alter both brain development and function. The development of targeted biological treatments requires an understanding of the molecular signature directly related to the pathogenesis one is attempting to alter. However, molecular transcriptome alterations related to region, age, and cellular pathology in ASD compared to the typically developing brain remains completely unknown and unexplored. In fact, no study to date has focused on cell-specific gene patterns in any brain region at any age in ASD. The study of a large population of live individuals using MRI and molecular studies of blood can provide us with surrogate information on global brain changes. However, postmortem human brain tissue from ASD and unaffected individuals is necessary to uncover the direct link between specific cellular pathology and underlying molecular transcriptomic alterations. To begin to address this critical gap in knowledge, we propose a pilot study to assess the feasibility of this novel avenue of investigation: 1) Characterize cellular alterations with stereological measures of neuronal and microglial cell number and size in superior temporal sulcus (STS), a key "social brain" region, and contrast findings with adjacent primary auditory cortex (PAC). 2) Identify region- and cell-specific alterations in gene expression in these regions using laser capture microscopy and cell suspension techniques to isolate neurons and microglia for RNA-sequencing. In summary, the overarching goal of this research is to combine markers of cellular and transcriptomic alterations in specific brain regions and cell types to paint a detailed picture of the molecular mechanisms that underlie aberrant brain development in ASD, thus identifying molecular signatures that can be investigated in larger populations and targeted for interventions across lifespan.

 描述（通过应用程序提供）：大多数患有自闭症谱系障碍（ASD）（ASD）的大脑结构和功能的变化开始生命的早期，但是在发育过程中它们在整个生命周期内都会继续变化。这些与年龄有关的差异是区域特定的，并且在高阶，社会和情感大脑区域中的大多数证据。我们的纵向磁共振成像（MRI）研究表明，在这五个爱情中，ASD儿童的暂时性皮质生长最大程度地偏离了典型的发育，始于2年的生命。尽管这种现象是童年期间最多的证据，但我们发现整个生命周期中的细胞改变会继续下去。在ASD成年人的临时皮质和皮质下区域中，神经元数量减少，ASD大脑的一部分具有过多的小胶质细胞激活，表明大脑中的免疫反应异常。这些差异是在童年时期存在还是由于退化性细胞损失的结果仍然是一个谜。显然，在ASD脑中发现的结构和细胞改变因区域和年龄而有所不同，并且是细胞特异性的。 ASD大脑的异质性和变化的病理学提出了转化生物疗法以改变大脑发育和功能的并发症。靶向生物学处理的发展需要了解与试图改变的发病机理直接相关的分子特征。然而，与典型发育的大脑相比，与ASD区域，年龄和细胞病理相关的分子转录组改变仍然是完全未知和意外的。实际上，迄今为止，尚无研究的任何大脑区域的细胞特异性基因模式。使用MRI和血液分子研究对大量活个体的研究可以为我们提供有关全球大脑变化的替代信息。但是，从ASD和未受影响的个体的死后人脑组织对于发现特定的细胞病理与潜在的分子转录组改变之间的直接联系是必要的。为了开始解决这一知识的关键差距，我们提出了一项试点研究，以评估这种新颖的投资途径的可行性：1）以神经元和小胶质细胞的立体量度和小胶质细胞数量和大小的临时sulcus（STS）（STS）（STS）（社交大脑），一个关键的“社交大脑”区域以及与邻近的原始Audy Cortitory Cortecity Cortexex（Pac）相比）的细胞变化的特征。 2）使用激光捕获显微镜和细胞悬浮技术在这些区域中确定基因表达的区域和细胞特异性改变，以分离神经元和小胶质细胞，以进行RNA序列。总而言之，这项研究的总体目标是结合特定大脑区域和细胞类型中细胞和转录组改变的标志物，以绘制ASD中脑发育异常的分子机制的详细图片，从而识别分子签名，从而确定可以在较大群体中研究的分子签名，并针对跨越寿命的人群进行靶向靶向。