KINETICS OF CELL PROLIFERATION IN THE STRIATUM

纹状体细胞增殖动力学

• 批准号: 2445809
• 负责人: PRADEEP G BHIDE
• 金额: $ 10.86万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2445809
• 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

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.

研究计划的长期目标是描述 调节神经元生成的机制， 纹状体（前脑基底神经节的组成部分）， 正常发育或病理状态下。这些目标将是 分三个阶段实现：个体发育变异的幅度 细胞动力学参数（调节细胞生长过程的变量） 将定量纹状体祖细胞的变化， 将与世代速率和表型的变化有关 后代的多样性;基于这些数据， 将开发纹状体细胞发生;使用体外模型， 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将是 表征了这些数据对于分析 特定基因产物的影响（例如，亨廷顿病基因）或 特定的生化物质（如生长因子、神经递质或 神经肽）对纹状体发育的影响，特别是如果转基因动物 适用于这种分析的模型变得可用。方法如 上面描述的那些已经被用于非神经系统的研究 取得了显著的成功，但不是在细胞生成的研究中， 纹状体 这一应用的实验将是三个阶段中的第一个阶段 上面提到的。他们会估计每一天的纹状体 神经发生期，细胞动力学参数的平均值， 神经节隆起中的祖细胞（纹状体的胚胎来源） 细胞）;定量从神经节细胞输出的速率， 隆起，并确定两类的生成时间， 纹状体神经元个体发育中的变异 细胞动力学参数将与细胞增殖速率的变化有关。 细胞产量和表型多样性的后代产生在 相应的时期。这些数据将作为关键的基线， 用于开发细胞生成的体外模型的参数 纹状体目前使用的主要技术 实验将在有丝分裂周期的同一阶段标记细胞， 溴脱氧尿苷和/或氚化胸苷，并鉴定标记的 来自神经节隆起或体的组织切片中的细胞 纹状体的免疫细胞化学或放射自显影方法。数量和 不同发育时期标记细胞的空间分布 将进行分析，以估计细胞动力学参数和 细胞输出这些技术将与 免疫细胞化学测定纹状体的生成时间 含有P物质或脑啡肽的神经元，神经元类型 选择性耗尽了亨廷顿氏病。