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White Matter Pathology in Angelman Syndrome and Its Potential as an Outcome Measure in Clinical Trials

安杰曼综合征的白质病理学及其作为临床试验结果衡量指标的潜力

基本信息

批准号：
9974549
负责人：
Heather Cody Hazlett
金额：
$ 61.27万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-12 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974549
关键词：
Adult Alleles Anatomy Angelman Syndrome Axon Behavior assessment Behavioral Biological Markers Caliber Cells Child Clinic Clinical Clinical Trials Coupled Data Defect Development Diffusion Diffusion Magnetic Resonance Imaging Disease Electron Microscopy Evaluation Goals Growth Human Impairment Individual Intellectual functioning disability Intervention Lead Link Magnetic Resonance Imaging Microcephaly Modality Modeling Motor Motor Skills Neurodevelopmental Disorder Neurons Outcome Outcome Measure Pathology Pathway interactions Patients Phenotype Pilot Projects Prevention Prosencephalon Proteins Radial Recovery Research Severities Speech System Testing Therapeutic Intervention UBE3A gene United States axon growth behavioral outcome behavioral phenotyping data modeling density expectation human model imaging study insight light microscopy motor behavior motor deficit motor disorder motor impairment mouse model myelination neuroimaging novel postnatal prevent skill acquisition therapeutic biomarker therapy outcome tractography treatment strategy white matter

项目摘要

PROJECT SUMMARY White matter (WM) pathway deficits are common in neurodevelopmental disorders, including Angelman syndrome (AS). The few imaging studies performed to date suggest that AS individuals have loss of WM volume and possibly delayed myelination. However, these abnormalities remain poorly defined, making it difficult to link them to behavioral phenotypes and, consequently, to establish their value as therapeutic biomarkers. Accordingly, a major unmet need is to elucidate the anatomical and pathophysiological basis of abnormal WM development in AS, and to test whether prevention or reversal of WM deficits leads to improvement in core behavioral domains. Our preliminary light and electron microscopy studies of AS model mice suggest that impairments in axon growth precipitate delays in myelination and culminate in lifelong deficits in axon caliber and WM volume. Our preliminary magnetic resonance imaging (MRI) coupled with diffusion tensor imaging (DTI) data from children with AS demonstrate a conserved deficit in WM volume and indicate a similar delay in myelination. Importantly, we find in motor systems that the degree of WM insult strongly correlates with the severity of motor dysfunction in AS patients. Here we will leverage the experimental tractability of AS model mice and our unique access to AS individuals through the UNC Angelman Syndrome Clinic (the first AS clinic established in the United States) to reveal the developmental basis of WM deficits in AS. Specifically, we will test our data-driven central hypothesis that WM pathway abnormalities and associated AS phenotypes arise from deficits in the radial growth of axons and associated delays in myelination, which can be prevented by reinstatement of UBE3A expression in neurons. To achieve our goals, we aim to (1) Define the developmental trajectory and underlying anatomical basis for WM deficits in AS model mice, (2) Establish neuroimaging correlates of these deficits and test the hypothesis that they are a biomarker for motor phenotypes in children with AS, and (3) Model the efficacy of early versus late therapeutic intervention toward the normalization of WM development and motor outcomes in AS. Through our research, we seek to inform treatment strategies for AS and to establish WM integrity as a novel outcome measure for upcoming AS clinical trials.

项目总结