VISUAL NEURON DEATH--MOLECULES REGULATING COMPETITION

描述(改编自摘要)：在开发 脊椎动物神经系统，有强烈的细胞增殖和 积累。因此，令人有点惊讶的是，一个巨大的(50-70 神经元的丧失通常也会发生在发育过程中。这 正常细胞死亡的时期与轴突神经支配相吻合 突触靶组织。此外，这一过程通常还在继续。 在此期间，神经元也接受来自 细胞。与坏死不同，发育中的细胞死亡需要活跃的 表达新的信使核糖核酸或蛋白质以启动和完成基因 细胞自杀程序。这个项目的长期目标是 阐明细胞和分子机制，调节 脑发育期间神经元的程序性细胞死亡(PCD)。PCD是 据信在数字上匹配突触前和突触后起作用 神经系统的组成部分，以满足患者的功能需求 有机体。这项建议侧重于通常使用的机制 有选择地消除或保留建筑中的未成熟神经元 脊椎动物的视觉系统。这项提议的一个独特之处是 将神经营养因子基因定向转移到选定的组织或在 选定的发展时期。我们打算在地区范围内限制 这些基因的过度表达或缺失以测试它们的生理 在调节PCD方面的相关性。鸟类的神经系统是治疗这些疾病的理想选择。 实验是因为神经元谱系可以选择性地转基因和 从大脑发育的最早阶段就进行了实验操作 在卵子里。小鸡嵌合体将由正常和 转染脑成分以实验控制表达 突触前和靶突触后组织中的外源基因。 此外，一个成熟的神经元竞争模型 还将研究具有双目视觉的哺乳动物的存活率。 通过基因工程过多表达生存因子的细胞系将 被植入仓鼠的视觉系统。植入物将被用于 解剖靶组织和传入组织的个体贡献 神经节细胞在视网膜内和视网膜间的竞争 生死存亡。最后，对分离的神经元亚群进行体外分析。 将提供对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。总而言之，这是 综合分析将提供对 神经元竞争分子调控的工作假说 和PCD。有趣的是，神经元具有相似的特异性和形态 PCD是由多种人类疾病(包括视网膜炎)引起的 色素变性，阿尔茨海默病，肌萎缩侧索硬化症， 帕金森氏症和截瘫)。因此，对 决定正常发育的PCD的机制也可能是 尤其有助于找到策略来减少或补偿 与这些人类疾病相关的特定神经元丢失。

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.