White Matter Fiber Tract Pathology in a Genetically-Defined Neurodevelopmental Disorder

项目摘要 白色物质通路缺陷常见于神经发育障碍，包括Angelman综合征 （AS）。迄今为止进行的少数影像学研究表明，AS患者有广泛的白色物质 缺陷，包括体积损失和可能延迟的髓鞘形成。然而，AS患者的白色物质缺乏 仍然定义不清，难以将其与行为表型联系起来，因此， 它们作为治疗生物标志物的价值。因此，一个主要的未满足的需求是阐明解剖学和生物学的特征。 AS中白色物质缺乏的病理生理学基础，并测试是否预防或逆转这些 缺陷导致核心行为领域的改善。来自AS儿童的初步数据显示， 白色物质体积和白色物质纤维束完整性的减少，以及强相关性 这些WM缺陷和运动延迟之间的联系。我们在AS模型小鼠中的初步数据表明， 表现出白色物质途径损伤，重现了AS个体中发现的那些。白色物质 AS模型小鼠中的缺陷在所有分析水平上都是可定量的，从宏观磁共振 磁共振成像（MRI）结合扩散张量成像（DTI）和超微结构电子显微镜（EM）。这里我们 将利用AS模型小鼠的实验易处理性和我们独特的AS个体访问， 在美国成立的第一家AS诊所（The First AS Clinic）， AS中白色物质缺乏的解剖学和病理生理学基础。我们的研究构成了 将人类神经发育障碍中的白色物质缺陷与其小鼠模型直接联系起来的新努力， 并将测试我们的数据驱动的中心假设，即白色物质通路损伤和相关的AS 表型由髓鞘形成延迟和大直径轴突的丢失引起， 恢复神经元中的UBE3A表达。为了实现我们的目标，我们的目标是（1）描绘白色物质 通路缺陷，并检验它们是AS儿童运动表型的生物标志物的假设，（2） 明确AS模型中白色物质缺陷的发育轨迹和潜在解剖学基础 小鼠，和（3）对早期与晚期治疗干预对白色正常化的功效进行建模 AS中的物质缺陷和运动结果。通过我们的研究，我们寻求为AS的治疗策略提供信息。 并将WM完整性作为即将进行的AS临床试验的新终点。

PROJECT SUMMARY White matter pathway deficits are common in neurodevelopmental disorders, including Angelman syndrome (AS). The few imaging studies performed to date suggest that AS individuals have generalized white matter deficits, including loss of volume and possibly delayed myelination. However, white matter deficits in AS 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 for white matter deficits in AS, and to test whether prevention or reversal of these deficits leads to improvement in core behavioral domains. Preliminary data from children with AS show reductions in white matter volume and integrity of white matter fiber tracts, as well as strong relationships between these WM deficits and motor delays. Our preliminary data in AS model mice demonstrate that they exhibit white matter pathway impairments that recapitulate those found in AS individuals. The white matter deficits in the AS model mice are quantifiable at all levels of analysis, from macroscopic magnetic resonance imaging (MRI) coupled with diffusion tensor imaging (DTI) to ultrastructural electron microscopy (EM). 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 precise anatomical and pathophysiological underpinnings of white matter deficits in AS. Our research constitutes a novel effort to directly link white matter deficits in a human neurodevelopmental disorder with its mouse model, and will test our data-driven central hypothesis that white matter pathway impairments and associated AS phenotypes arise from delayed myelination and a loss of large-diameter axons that can be prevented by reinstatement of UBE3A expression in neurons. To achieve our goals, we aim to (1) Delineate white matter pathway deficits and test the hypothesis that they are a biomarker for motor phenotypes in children with AS, (2) Define the developmental trajectory and underlying anatomical basis for white matter deficits in AS model mice, and (3) Model the efficacy of early versus late therapeutic intervention toward the normalization of white matter deficits and motor outcomes in AS. Through our research, we seek to inform treatment strategies for AS and to establish WM integrity as a novel endpoint for upcoming AS clinical trials.