VISUAL NEURON DEATH--MOLECULES REGULATING COMPETITION

描述（改编自摘要）：在开发期间， 脊椎神经系统，有强烈的细胞增殖， 积累 因此，令人惊讶的是，一个巨大的（50-70 神经元的损失通常也发生在发育过程中。 这 正常细胞死亡的时期与轴突神经支配相一致， 突触靶组织。 此外，这一过程往往还在继续 在这段时间里，神经元也从 细胞 与坏死不同，发育细胞死亡需要活性的 表达新的mRNA或蛋白质以启动和完成遗传修饰。 细胞自杀计划 该项目的长期目标是 阐明调节细胞和分子机制， 脑发育过程中神经元的程序性细胞死亡（PCD）。 PCD是 据信在突触前和突触后的数字匹配中发挥作用 神经系统的组成部分，以满足功能的需求， 有机体 本建议侧重于通常使用的机制 选择性地消除或保留未成熟的神经元 脊椎动物视觉系统。该提案的一个独特之处在于， 将神经营养因子基因靶向转移至选定的组织或 选择发展时期。 我们打算在区域范围内限制 这些基因的过表达或缺失，以测试它们的生理活性。 与PCD的关系。鸟类的神经系统非常适合 因为神经元谱系可以被选择性地转染， 从大脑发育的最早阶段就开始实验性地操作 在卵中。 小鸡嵌合体将由正常和 转染的大脑成分，以实验性地控制表达 外源基因在突触前和目标突触后组织。 此外，一个建立良好的神经元竞争模型， 还将研究具有双眼视觉的哺乳动物的存活情况。 细胞系，基因工程过表达生存因子，将 植入仓鼠的视觉系统 植入物将用于 解剖靶组织和传入组织的个体贡献， 视网膜内和视网膜间神经节细胞的竞争， 生存 最后，用分离的神经元亚群进行体外测定， 将提供一个实验的直接影响的分析 在没有其他细胞类型的情况下进行操作。 总的来说，这 综合分析将提供一个全面的审查， 神经元竞争的分子调节工作假说 和PCD。有趣的是，神经元的相似特异性和形态 PCD由多种人类疾病（包括视网膜炎）诱导 色素沉着症，阿尔茨海默病，肌萎缩侧索硬化症， 帕金森病和截瘫）。 所以，理解 决定正常发育PCD的机制也可能是 特别有助于找到减少或补偿 与这些人类疾病相关的特定神经元损失。

DESCRIPTION (adapted from abstract) : During the development of the vertebrate nervous system, there is intense cell proliferation and accumulation. It is therefore somewhat surprising that a massive (50-70 percent) loss of neurons also normally occurs during development. This period of normal cell death coincides with the axonal innervation of synaptic target tissues. In addition, this process often continues through the period in which neurons also receive afferent input from cells. Unlike necrosis, development cell death requires the active expression of new mRNA or protein to initiate and complete a genetic program of cell suicide. The long term goal of this project is to elucidate the cellular and molecular mechanisms that regulate the programmed cell death (PCD) of neurons during brain development. PCD is believed to play a role in numerically matching the pre and post synaptic components of the nervous system to meet the functional demand of the organism. This proposal focuses on the mechanisms that are normally used to selectively eliminate or retain immature neurons in the construction of the vertebrate visual system. A unique aspect of this proposal is the targeted transfer of neurotropic factor genes to selected tissues or at selected period of development. We intend to regionally restrict the overexpression or deletion of these genes to test their physiological relevance in regulating PCD. The avian nervous system is ideal for these experiments because neuronal lineages can be selectively transfected and experimentally manipulated from the earliest stages of brain development in ovo. Chick chimeras will be made with a mosaic of normal and transfected brain components to experimentally control the expression of foreign genes in both presynaptic and target postsynaptic tissues. In addition, a well established model of neuronal competition for survival will also be investigated in mammals with binocular vision. Cell lines, genetically engineered to overexpress survival factors, will be implanted into the hamster visual system. Implants will be used to dissect the individual contributions of target and afferent tissues in both the intraretinal and interretinal competition of ganglion cells for survival. Lastly, in vitro assays with isolated neuronal subpopulations will provide an analysis of the direct effects of experimental manipulations in the absence of other cell types. Taken together, this integrative analysis will provide a comprehensive examination of a working hypothesis on the molecular regulation of neuronal competition and PCD. Interestingly, a similar specificity and morphology of neuronal PCD is induced by a variety of human disease (including Retinitis Pigmentosa, Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's Disease and Paraplegia). Thus, an understanding of the mechanisms that determine normal developmental PCD may also be especially helpful in finding strategies to reduce or compensate for the specific neuronal losses associated with these human diseases.