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 神经元数量似乎是通过平衡 神经元的产生和神经元的存活。 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 神经元的产生尚未确定。 建议的目标 研究的目的是确定促有丝分裂和促进生存的 多肽生长因子的活性相互作用， 神经系统发育过程中的神经元数量。 完成 神经发生和神经元存活的调节将是 在再生的感觉上皮中检查， 上皮细胞（OE）的小鼠。 初步研究表明，两个家庭的成员， 多肽生长因子在调节神经元中可能是重要的 胚胎OE的RNA分析 已经证明酪氨酸激酶的存在成纤维细胞生长 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（bFGF）似乎促进嗅神经元的增殖 OE组织培养物中的前体，表明FGF在 调节神经发生。 亲和交联研究表明 至少2种神经营养因子（NT）的受体，脑源性 神经营养因子和神经营养素-3存在于OE中。 将进行体内和体外实验以确定如何 FGF和NT的作用调节OE中的神经元数目。 NT和FGF的生物活性将通过以下测定： 评估其对确定的OE细胞群的影响，使用新的 纯化和培养这些来自远系繁殖的细胞的方法， 转基因小鼠 营养因子作用的细胞靶点将是 通过功能测定和检测 生长因子受体在确定的细胞，使用分子 对不同发育阶段的细胞具有特异性的标记物， OE神经源性通路。 评估营养因子在体内的作用 发现在体外有活性，OE中因子的表达，其 支持组织，它的突触目标（嗅球）将是 考察 将进行体内置换研究， 确定体外鉴定的特定因素是否可以 预防或改善嗅觉神经元损伤引起的嗅觉退化 受体神经元 这项工作将有助于理解和 治疗神经系统发育障碍，如 神经管缺陷，通过提供关于神经元如何 在开发过程中，数量受到控制。 通过确定是否 给予特定的营养因子可以防止神经元的 变性，这项工作可能有助于开发治疗方法， 神经退行性疾病和创伤诱导的 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.