Comparative Morphology of Neuronal Ceroid Lipofuscinosis

神经元蜡质脂褐质沉积症的比较形态学

基本信息

批准号：
6789345
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
项目类别：
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/6789345
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

项目摘要

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）神经元蜡样脂褐质沉积症 (NCL) 是进行性、致命性的神经退行性溶酶体贮积症统称为最常见的儿童遗传性神经退行性存储障碍每 12,500 个五胞胎中就有 1 个发生率。目前还鲜为人知关于哪些神经元群在 NCL 中受到影响以及它们如何正常结构受到损害。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共同点通过将患者组织与新开发的小鼠模型进行比较来主题 NCL。该项目的主要目标是确定青少年 NCL (JNCL) 的病理变化，这是最常见的形式紊乱。目前缺乏此信息，但绝对必要用于了解疾病过程并有效定位和评估新治疗方法的功效。我们将使用公正的体视学方法来表征区域、核周、树突和突触水平小鼠和人类神经病理学变化的程度 JNCL 组织。我们将通过以下具体目标来实现我们的目标：1) 量化细胞体积和总细胞组织的变化海马体、小脑和皮质分区； 2) 检查神经元胞体更详细地确定这些地区的变化程度和时间 i) 神经元总数和 ii) GABA 能的数量和体积中间神经元，一个神经元亚群，我们的初步证据表明在这种疾病中受到显着影响，并且。 iii) 扩展此对具有共同表型特征的神经元群体进行分析； 3）定义树突乔木和突触接触的病理变化由这些神经元产生； 4) 确定神经胶质激活的程度和 JNCL 中的炎症反应及其与病理相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的临床相关性以进行测试潜在的治疗方法； b) 允许更有效地制定治疗策略适当的神经元群体； c）有可能揭示新的种群受影响的神经元； d) 建立一系列必要的病理标志用于评估治疗效果。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis.

婴儿神经元蜡质脂褐质沉着症小鼠模型中丘脑和皮质的连续神经元丢失。

DOI：
发表时间：
2007-01
期刊：
影响因子：
6.1
作者：
Kielar, Catherine;Maddox, Lucy;Bible, Ellen;Pontikis, Charlie C;Macauley, Shannon L;Griffey, Megan A;Wong, Michael;Sands, Mark S;Cooper, Jonathan D
通讯作者：
Cooper, Jonathan D

Progress towards understanding disease mechanisms in small vertebrate models of neuronal ceroid lipofuscinosis.

了解神经元蜡状脂褐质沉积症小型脊椎动物模型疾病机制的进展。

DOI：
发表时间：
2006-10
期刊：
影响因子：
0
作者：
Cooper, Jonathan D;Russell, Claire;Mitchison, Hannah M
通讯作者：
Mitchison, Hannah M

Progressive thalamocortical neuron loss in Cln5 deficient mice: Distinct effects in Finnish variant late infantile NCL.

Cln5 缺陷小鼠进行性丘脑皮质神经元丢失：对芬兰变异型婴儿晚期 NCL 的独特影响。

DOI：
发表时间：
2009-05
期刊：
影响因子：
6.1
作者：
von Schantz C;Kielar C;Hansen SN;Pontikis CC;Alexander NA;Kopra O;Jalanko A;Cooper JD
通讯作者：
Cooper JD

Adeno-associated virus 2-mediated gene therapy decreases autofluorescent storage material and increases brain mass in a murine model of infantile neuronal ceroid lipofuscinosis.

腺相关病毒 2 介导的基因治疗可减少婴儿神经元蜡质脂褐质沉积症小鼠模型中的自发荧光储存物质并增加脑质量。

DOI：
发表时间：
2004-07
期刊：
影响因子：
0
作者：
Griffey, Megan;Bible, Ellen;Vogler, Carole;Levy, Beth;Gupta, Praveena;Cooper, Jonathan;Sands, Mark S
通讯作者：
Sands, Mark S

IgG entry and deposition are components of the neuroimmune response in Batten disease.

IgG 进入和沉积是 Batten 病神经免疫反应的组成部分。

DOI：
发表时间：
2007-02
期刊：
影响因子：
6.1
作者：
Lim, Ming J;Alexander, Noreen;Benedict, Jared W;Chattopadhyay, Subrata;Shemilt, Stephen J A;Guerin, Christopher J;Cooper, Jonathan D;Pearce, David A
通讯作者：
Pearce, David A