TROPHIC FACTOR CONTROL OF NEURON PRODUCTION AND SURVIVAL

神经元数量的精确调节是神经系统的一个标志 发展。神经元的数量似乎是通过平衡 发育过程中神经元的产生和存活。 已知多肽生长因子介导神经元存活 神经系统的许多区域，但它们在控制 神经元的产生尚不确定。建议的目标是 研究是为了确定有丝分裂和促进生存是如何 多肽生长因子的活性相互作用调节 神经系统发育过程中的神经元数量。要完成 这将是对神经发生和神经元存活的调节 在再生的感觉上皮细胞中检查，嗅觉 小鼠上皮(OE)。 初步研究表明，两个家族的成员 多肽生长因子可能在神经元调控中发挥重要作用 在OE的生产和生存。胚胎卵母细胞中RNA的分析 已经证明了酪氨酸激酶成纤维细胞的存在 因子受体。为了支持这一想法，基本的成纤维细胞生长 碱性成纤维细胞生长因子促进嗅神经细胞增殖 OE组织培养中的前体，提示FGFs在 调节神经发生。亲和力交联研究表明 至少2种神经营养因子(NTS)的受体，大脑来源 神经营养因子和神经营养因子-3存在于OE中。两个都在 将进行体内和体外实验，以确定如何 FGFs和NTs的作用调节OE中的神经元数量。 NTS和FGFs的生物活性将通过以下方式确定 评估它们对已定义的OE细胞群体的影响，使用新的 纯化和培养这些细胞的程序从异种和 转基因小鼠。营养因子作用的细胞靶点将是 由功能分析和通过检查 利用分子生物学技术，鉴定细胞中的生长因子受体 不同发育阶段细胞的特异性标记物 OE神经发生通路。评估营养因子在体内的作用 发现在体外具有活性，因子在OE中的表达，其 支持组织，其突触靶点(嗅球)将是 检查过了。将进行体内替代研究，以 确定体外鉴定的特定因子是否可以 预防或改善手术诱导的嗅觉变性 感受器神经元。这项工作将有助于理解和 神经系统发育障碍的治疗，如 神经管缺陷，通过提供关于神经元如何 数量是在开发过程中控制的。通过确定是否 给予特定的营养因子可以防止神经元 退化，这项工作可能有助于开发治疗 神经退行性疾病和创伤性退行性变 神经元。

Precise regulation of neuron number is a hallmark of nervous system development. neuron number appears to be achieved by a balance of neuron production and neuron survival during development. Polypeptide growth factors are known to mediate neuron survival in many areas of the nervous system, but their role in controlling neuron production is undetermined. The goal of the proposed research is to determine how the mitogenic and survival-promoting activities of polypeptide growth factors interact to regulate neuron number during nervous system development. To accomplish this, regulation of neurogenesis and neuron survival will be examined in a regenerating sensory epithelium, the olfactory epithelium (OE) of the mouse. Preliminary studies indicate that members of 2 families of polypeptide growth factors may be important in governing neuron production and survival in OE. Analysis of RNA from embryonic OE has demonstrated the presence of tyrosine kinase Fibroblast Growth Factor Receptors. In support of this idea, basic Fibroblast Growth Factor (bFGF) appears to increase proliferation of olfactory neuron precursors in OE tissue cultures, suggesting a role of FGFs in regulating neurogenesis. Affinity crosslinking studies indicate that receptors for at least 2 Neurotrophins (NTs), Brain Derived Neurotrophic Factor and Neurotrophin-3, are present in OE. Both in vivo and in vitro experiments will be performed to determine how the actions of FGFs and NTs regulate neuron number in the OE. Biological activities of NTs and FGFs will be determined by assessing their effects on defined OE cell populations, using new procedures for purifying and culturing these cells from outbred and transgenic mice. Cellular targets of trophic factor action will be defined both by functional assays and by examining expression of growth factor receptors in identified cells, using molecular markers specific for cells at different developmental stages in the OE neurogenic pathway. To assess in vivo roles of trophic factors found to be active in vitro, expression of factors in OE, its supporting tissue, and its synaptic target (olfactory bulb) will be examined. In vivo replacement studies will be performed to determine whether specific factors, identified in vitro, can prevent or ameliorate surgically-induced degeneration of olfactory receptor neurons. This work will aid in the understanding and treatment of developmental disorders of the nervous system, such as neural tube defects, by providing information about how neuron number is controlled during development. By determining whether administration of specific trophic factors can prevent neuronal degeneration, this work may aid in the development of therapies for both neurodegenerative diseases and trauma-induced degeneration of neurons.