Comparative Morphology of Neuronal Ceroid Lipofuscinosis

描述(由申请人提供) 神经性蜡样脂褐素沉积症(NCLS)是进行性的，致命的 神经退行性溶酶体储存障碍共同代表 儿童时期最常见的遗传性神经退行性存储障碍 发病率高达每12,500名新生儿中就有1名。目前还鲜有人知道 关于NCLS中哪些神经元群体受到影响，以及他们的 正常的结构受到了损害。这些数据可以通过系统地 分析受影响中枢神经系统的细胞成分并寻找共同之处 通过比较患者的组织和新开发的小鼠模型来研究主题 NCL。该项目的主要目标是确定 幼年型NCL(JNCL)的病理变化 无序。目前缺乏这方面的信息，但这是绝对必要的 用于了解疾病过程并有效地确定目标和评估 新的治疗方法的有效性。我们应该不偏不倚地 体视学方法论在区域、周缘、树枝上的特征 和突触水平：小鼠和人神经病变的程度 JNCL组织。我们将以以下具体目标完成目标：1) 为了量化在体积和总的蜂窝组织的变化 海马区、小脑和皮质亚区；2)检查神经元胞体 在这些地区更详细地定义变化的范围和时间 神经元总数和GABA能神经元的数量和体积 中间神经元，我们的初步证据表明， 适应症在这种疾病中受到显著影响，并且。三)延长这一期限 对具有共同表型特征的神经元群体进行分析； 3)确定树突和突触接触的病理变化 4)测定神经胶质细胞的激活程度和 JNCL的炎症反应及其时间与病理的关系 神经元的变化。从这些比较研究中获得的信息将 A)进一步验证要测试的这些动物模型的临床相关性 潜在疗法；b)允许更有效地针对治疗战略 适当的神经元种群；c)潜在地揭示新的种群 受影响的神经元；以及d)建立一系列必要的病理标志 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.