Comparative Morphology of Neuronal Ceroid Lipofuscinosis

描述（由申请人提供） 神经元蜡样脂褐质沉积症（NCL）是一种进行性、致死性疾病， 神经退行性溶酶体贮积症，共同代表了 儿童期最常见的遗传性神经退行性记忆障碍， 发病率高达1/12，500 5次分娩。目前还鲜为人知 关于哪些神经元群体在NCL中受到影响以及它们如何受到影响， 正常的结构会受到影响这些数据可以通过系统地 分析受影响的中枢神经系统的细胞成分，并寻找共同的 通过比较患者的组织和新开发的小鼠模型， NCL。该项目的主要目标是确定 青少年NCL（JNCL）的病理变化，最普遍的形式， disorder.这方面的信息目前还缺乏，但绝对是必不可少的 了解疾病过程，有效地定位和评估 新的治疗方法的有效性。我们将使用无偏 体视学方法来表征区域、核周、树突 和突触水平的神经病理变化的程度，在小鼠和人类 JNCL组织。我们将通过以下具体目标来实现我们的目标：1） 为了量化的体积和毛细胞组织的变化， 海马、小脑和皮质亚区; 2）检查神经元索马 在这些地区，更详细地确定变化的程度和时间， i）总神经元群体和ii）GABA能的数量和体积 interneurons，我们的初步证据表明， 表明在这种疾病中受到显著影响，并且。（三）扩大这 分析具有共同表型特征的神经元群体; 3)明确树突和突触接触的病理变化 4）为了确定胶质细胞活化的程度， JNCL中的炎症反应及其与病理 神经元的变化。从这些比较研究中获得的信息将 a）进一步验证这些动物模型的临床相关性以测试 潜在的治疗方法; B）允许更有效的治疗策略靶向 适当的神经元群体; c）潜在地揭示新的神经元群体， 受影响的神经元;和d）建立一系列病理标志， 用于评估治疗效果。

DESCRIPTION (provided by applicant) The neuronal ceroid lipofuscinoses (NCLs) are progressive, fatal neurodegenerative lysosomal storage disorders that collectively represent the most common inherited neurodegenerative storage disorder of childhood with an incidence of up to 1 in 12,500 five births. There is currently little known regarding which neuronal populations are affected in the NCLs and how their normal structure is compromised. These data can be obtained by systematically analyzing the cellular components of the affected CNS and looking for common themes by comparing tissue from patients to newly developed mouse models of NCL. The main goals of this project are to define the extent and progression of pathological changes in juvenile NCL (JNCL), the most prevalent form of the disorder. This information is currently lacking, but is absolutely essential for understanding disease processes and effectively targeting and evaluating the efficacy of novel therapeutic approaches. We shall use unbiased stereological methodology to characterize at a regional, perikaryal, dendritic and synaptic level the extent of neuropathological changes in murine and human JNCL tissue. We will accomplish our goals with the following specific aims: 1) To quantify changes in the volume and gross cellular organization of the hippocampus, cerebellum and cortical sub-regions; 2) To examine neuronal soma in these regions in more detail to define the extent and timing of changes in the number and volume of i) the total neuronal population and ii) GABAergic interneurons, a neuronal sub population which our preliminary evidence indicates are significantly affected in this disorder, and. iii) extend this analysis to neuronal populations that share common phenotypic characteristics; 3) To define pathologic changes in the dendritic arbor and synaptic contacts made by these neurons; 4) To determine the extent of glial activation and kfiammatory responses in JNCL and their timing in relation to pathological changes in neurons. The information gained from these comparative studies will a) further validate the clinical relevance of these animal models to test potential therapies; b) permit more efficient targeting of treatment strategies to appropriate neuronal populations; c) potentially reveal novel populations of affected neurons; and d) establish a series of pathological landmarks essential for evaluating therapeutic efficacy.