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The nature of astrocyte heterogeneity in RTT

RTT 中星形胶质细胞异质性的本质

基本信息

批准号：
8996606
负责人：
Benjamin Deneen
金额：
$ 19.7万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8996606
关键词：
Address Adult Affect Alzheimer&apos s Disease Angelman Syndrome Animals Astrocytes Autistic Disorder Autonomic Dysfunction Brain Brain Stem Brain region Breathing Carbon Dioxide Cells Clinical Coculture Techniques Data Development Disease Disease Progression Encephalopathies Epilepsy Functional disorder Future Gene Expression Gene Expression Profiling Genetic Transcription Glucose Health Heterogeneity Hindlimb Human In Vitro Intellectual functioning disability Knowledge Longevity Methyl-CpG-Binding Protein 2 Microglia Modeling Molecular Molecular Profiling Movement Disorders Mus Mutation Nature Nervous system structure Neurodevelopmental Disorder Neurologic Neurons Pathogenesis Phenotype Physiological Play Population Process Property Regulation Regulator Genes Reporter Rett Syndrome Role Schizophrenia Seizures Severity of illness Surface Antigens Work base cell type gene product insight male molecular subtypes mouse model mutant nervous system disorder novel marker respiratory synaptic function synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by a wide range of neurological deficits including, seizures, movement disorders, autonomic dysfunction, and marked breathing abnormalities. Nearly all cases of RTT are caused by de novo mutations in Methyl-CpG-binding protein 2 (MECP2), which functions as a global regulator of gene transcription. MeCP2 is highly expressed throughout the nervous system, and because the clinical features are associated with neuronal function, RTT has typically been assumed to be a disease of neurons. However, recent work has challenged this view, indicating that other cells within the nervous system such as astrocytes and microglia may play an important role in the pathogenesis of disease. While astrocytes directly contribute to key phenotypes associated with RTT, such as breathing and glucose sensitivity, the consequences of loss of MeCP2 on specific astrocyte sub-populations in these key regions remains completely undefined. Astrocytes have long been considered to be a uniform cell type, and in spite of recent findings indicating they perform diverse roles across the CNS, the nature of their cellular and functional heterogeneity remains shrouded in mystery. Using the brainstem and RTT as models for decoding these cellular and functional relationships, we hypothesize that MeCP2 plays a crucial role in key astrocyte subtypes within the brainstem, a brain region we have previously demonstrated to be critical in the genesis of breathing and other physiological abnormalities in RTT. To this end we have used FACS-based approaches to identify unique subpopulations of astrocytes in the adult brainstem. In specific aim 1 of this proposal, we will validate the presence of these populations in the brainstem and perform gene expression profiling on each subpopulation to decode their unique molecular signature. In specific aim 2 we will use similar FACS-based approaches to delineate astrocyte heterogeneity and their underlying molecular profiles in the brainstem of the RTT mouse. Through this work we will determine brainstem astrocyte heterogeneity and define the molecular profiles of these cells in normal and MeCP2 mutant populations, lending unprecedented insight into the nature of astrocyte heterogeneity in health and disease.

描述(申请人提供)：Rett综合征(RTT)是一种严重的神经发育障碍，其特征是广泛的神经功能障碍，包括癫痫、运动障碍、自主神经功能障碍和明显的呼吸异常。几乎所有的RTT病例都是由甲基CpG结合蛋白2(MECP2)的从头突变引起的，MECP2起着基因转录的全球调节作用。MeCP2在神经系统中高度表达，由于其临床特征与神经功能有关，RTT通常被认为是一种神经元疾病。然而，最近的工作挑战了这一观点，表明神经系统内的其他细胞，如星形胶质细胞和小胶质细胞，可能在疾病的发病机制中发挥重要作用。虽然星形胶质细胞直接参与了与RTT相关的关键表型，如呼吸和葡萄糖敏感性，但MeCP2基因缺失对这些关键区域特定星形胶质细胞亚群的影响仍然完全不清楚。长期以来，星形胶质细胞一直被认为是一种统一的细胞类型，尽管最近的发现表明，它们在对于中枢神经系统，它们的细胞和功能异质性的本质仍然是一个谜。使用脑干和RTT作为解码这些细胞和功能关系的模型，我们假设MeCP2在脑干中的关键星形胶质细胞亚型中发挥关键作用，我们之前已经证明，脑干是RTT中呼吸和其他生理异常发生的关键脑区。为此，我们使用了基于FACS的方法来识别成人脑干中独特的星形胶质细胞亚群。在本提案的具体目标1中，我们将验证这些种群在脑干中的存在，并对每个亚群进行基因表达谱分析，以解码其独特的分子特征。在特定的目标2中，我们将使用类似的基于流式细胞仪的方法来描绘RTT小鼠脑干中星形胶质细胞的异质性及其潜在的分子特征。通过这项工作，我们将确定脑干星形胶质细胞的异质性，并定义这些细胞在正常和MeCP2突变群体中的分子图谱，从而前所未有地深入了解星形胶质细胞在健康和疾病中的异质性的本质。