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KINETICS OF CELL PROLIFERATION IN THE STRIATUM

纹状体细胞增殖动力学

基本信息

批准号：
6149162
负责人：
PRADEEP G BHIDE
金额：
$ 2.5万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-07-01 至 2000-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6149162
关键词：
Huntington's disease autoradiography bromodeoxyuridine cell cycle corpus striatum developmental neurobiology early embryonic stage enkephalins ganglions immunocytochemistry laboratory mouse light microscopy neurogenesis substance P tritium

项目摘要

The long term goals of the research program are to characterize the mechanisms which regulate the generation of neurons destined for the corpus striatum (a component of the basal ganglia of the forebrain) during normal development or under pathological conditions. Those goals will be achieved in three stages: ontogenetic variation in the magnitudes of cytokinetic parameters (variables which regulate the process of cell generation) of striatal progenitors will be quantified and the variation will be related to the variation in the rate of generation and phenotypic diversity of the progeny; based on those data, an in vitro model of striatal cytogenesis will be developed; and using that in vitro model, the mechanisms by which intrinsic or extrinsic factors influence striatal cytogenesis under physiological or pathological conditions will be characterized. The data will be critically important for analyzing the effects of products of specific genes (e.g. Huntington's disease gene) or specific biochemical substances (e.g. growth factors, neurotransmitters or neuropeptides) on striatal development especially if transgenic animal models suitable for such analyses become available. Approaches such as those described above have been employed in research on non-neural systems with remarkable success, but not in research on cell generation in the corpus striatum. Experiments of this application will be the first of the three stages mentioned above. They will estimate for every day of the striatal neurogenetic period, the average values of the cytokinetic parameters of progenitors in the ganglionic eminence (embryonic source of striatal cells) in mice; quantify the rate of cellular Output from the ganglionic eminence, and determine the time of generation of two categories of striatal neurons. The Ontogenetic variation in the values of the cytokinetic parameters will be related to the variation in the rate of cellular output and phenotypic diversity of the progeny generated at the corresponding periods. Those data will serve as critical, baseline parameters for developing the in vitro model of cell generation in the corpus striatum. The principal technique to be used in the present experiments will be labeling cells in -phase of the mitotic cycle with bromodeoxyuridine and/or tritiated thymidine and identifying the labeled cells in tissue sections from the ganglionic eminence or the corpus striatum by immunocytochemical or autoradiographic methods. The number and spatial distribution of labeled cells at different developmental periods will be analyzed to estimate the cytokinetic parameters and the rate of cellular output. Those techniques will be combined with immunocytochemistry to determine the time of generation of striatal neurons containing substance P or enkephalin, the neuronal types selectively depleted in Huntington's disease.

该研究计划的长期目标是表征调节神经元生成的机制纹状体（前脑基底神经节的一个组成部分）正常发育或病理条件下。这些目标将是分三个阶段实现：个体发生变异的大小细胞因子参数（调节细胞过程的变量）纹状体祖细胞的一代）将被量化，并且变化与世代速率和表型的变异有关后代的多样性；基于这些数据，建立了一个体外模型纹状体细胞发生将得到发展；并使用该体外模型内在或外在因素影响纹状体的机制生理或病理条件下的细胞发生特点。这些数据对于分析非常重要特定基因（例如亨廷顿病基因）产物的影响或特定的生化物质（例如生长因子、神经递质或神经肽）对纹状体发育的影响，尤其是转基因动物适合此类分析的模型已经可用。诸如此类的方法上述那些已被用于非神经系统的研究取得了显着的成功，但在细胞生成研究方面却没有取得成功纹状体。该应用程序的实验将是三个阶段中的第一个阶段上面提到过。他们将估计纹状体的每一天神经发生期，细胞因子参数的平均值神经节隆起的祖细胞（纹状体的胚胎来源）细胞）在小鼠中；量化神经节细胞输出的速率并确定两类的产生时间纹状体神经元。值的个体发生变异细胞因子参数将与速率的变化有关细胞输出和后代的表型多样性对应的时期。这些数据将作为关键的基线用于开发体外细胞生成模型的参数纹状体。目前使用的主要技术实验将标记有丝分裂周期的细胞溴脱氧尿苷和/或氚化胸苷并鉴定标记的神经节隆起或体组织切片中的细胞通过免疫细胞化学或放射自显影方法检测纹状体。数量和不同发育时期标记细胞的空间分布将进行分析以估计细胞因子参数和速率细胞输出。这些技术将与免疫细胞化学测定纹状体的产生时间含有 P 物质或脑啡肽的神经元，神经元类型亨廷顿病中选择性耗尽。