Comparative Morphology of Neuronal Ceroid Lipofuscinosis

神经元蜡质脂褐质沉积症的比较形态学

• 批准号: 6471081
• 负责人: JONATHAN D COOPER
• 金额: $ 12.83万
• 依托单位: KING'S COLLEGE LONDON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6471081
• 关键词: brain morphology; cerebellum; clinical research; dendrites; glia; hippocampus; human tissue; immunocytochemistry; inflammation; interneurons; laboratory mouse; neuronal ceroid lipofuscinosis; neuropathology; pathologic process; postmortem; soma

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.

描述（由申请人提供） 神经元的ceroid脂肪曲霉（NCLS）是渐进的，致命的 神经退行性溶酶体储存障碍，共同表示 最常见的遗传性神经退行性储存障碍，儿童期 在12,500个五个出生中最多可发射1个。目前鲜为人知 关于哪些神经元群体在NCL中受到影响 正常结构受到损害。这些数据可以通过系统地获得 分析受影响的中枢神经系统的细胞成分并寻找常见 主题通过将患者的组织与新开发的小鼠模型进行比较 NCL。该项目的主要目标是定义 少年NCL（JNCL）的病理变化，这是最普遍的形式 紊乱。目前缺乏此信息，但绝对是必不可少的 理解疾病过程，并有效地定位和评估 新型治疗方法的功效。我们将使用公正 在区域，周期，树突状的特征的立体方法论 和突触水平的鼠和人类神经病理变化的程度 JNCL组织。我们将以以下特定目标来实现我们的目标：1） 量化体积和总体细胞组织的变化 海马，小脑和皮质子区域； 2）检查神经元体 在这些区域中，更详细地定义了变化的程度和时机 i）总体人群和ii）GABA能的数量和数量 神经元，一种神经元亚种群，我们的初步证据 表明在这种疾病中受到了显着影响。 iii）扩展此 对具有共同表型特征的神经元种群的分析； 3）定义树突状乔木和突触接触的病理变化 由这些神经元制成； 4）确定神经胶质激活的程度和 JNCL中的Kfiammatory响应及其与病理有关的时间 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测试的临床相关性 潜在疗法； b）允许更有效地针对治疗策略 适当的神经元种群； c）有可能揭示新的人群 受影响的神经元； d）建立一系列病理地标重要的 用于评估治疗功效。