NEUROTROPHIC SUPPORT IN AGING AND ALZHEIMERS DISEASE

描述：(申请人摘要)碱性成纤维细胞生长因子 成纤维细胞生长因子2(FGF2)是一种强有力的有丝分裂原和神经营养因子。成熟的中枢神经系统 这一因素的含量高得惊人。FGF2缺少一个 疏水信号肽序列，不能有效地从 未受刺激的健康细胞。我们的假设是损伤会导致 FGF2的释放，导致广泛表达的 跨膜成纤维细胞生长因子受体(FGFRs)。这一假设表明， FGF2在神经系统中的主要作用是作为早期的 细胞损伤的信号，并启动损伤反应，包括胶质细胞 激活和神经元的可塑性。以下具体目标将 测试提出的FGF2作用的生理模型： 目的1：检测损伤是否将FGF2释放到细胞外空间 并激活成纤维细胞生长因子受体。正常人细胞外FGF2水平的研究 受损的中枢神经系统将在体内使用高度敏感的FGF2进行量化 化验。同时检测损伤后成纤维细胞生长因子受体的激活情况。 目的2：测试单纯性质膜破裂或额外的 特定的输出机制导致损伤后FGF2的释放。FGF2 释放机制将在星形胶质细胞培养中进行表征。 目的3：检测FGF2基因敲除后大鼠海马区细胞构筑 转基因小鼠过表达FGF2是正常的，但这种损伤 响应会发生变化。免疫组织化学分析采用 将使用适当的标记物来确定FGF2缺失的影响 或在神经元存活、轴突萌发和胶质细胞上过度表达 正常和损伤小鼠海马区的反应性。 目的4：检测成纤维细胞生长因子2是否调节蛋白的表达 参与促进可塑性和修复。成纤维细胞生长因子2的作用 神经营养因子、细胞因子的基因敲除和过度表达 趋化因子将被确定。 目的5：检测FGF2在心脏的正常维持中是否起重要作用 老化的中枢神经系统。海马体体积，神经元和神经胶质细胞数量， 以及旧FGF2基因敲除和成纤维细胞生长因子-2基因敲除后海马区的细胞构筑 过度表达的小鼠将被确定。

DESCRIPTION: (Applicant's abstract) Basic fibroblast growth factor (FGF2) is a potent mitogen and neurotrophic factor. The mature CNS contains a surprisingly high level of this factor. FGF2 lacks a hydrophobic signal peptide sequence and is not efficiently released from unstimulated healthy cells. It is our hypothesis that injury causes the release of FGF2, resulting in the activation of widely expressed transmembrane FGF receptors (FGFRs). This hypothesis suggests that the main role of FGF2 within the nervous system is to serve as an early signal of cell injury and to initiate injury responses, including glial activation and neuronal plasticity. The following specific aims will test this proposed physiological model of FGF2 action: Aim 1: To test whether injury releases FGF2 into the extracellular space and activates FGF receptors. The levels of extracellular FGF2 in normal and injured CNS will be quantified in vivo using a highly sensitive FGF2 assay. FGF-receptor activation after injury will be also be measured. Aim 2: To test whether simple plasma membrane breach or additional specific export mechanisms cause the release of FGF2 after injury. FGF2 release mechanisms will be characterized in astrocyte cultures. Aim 3: To test whether the hippocampal cytoarchitecture of FGF2 knockout and FGF2 over-expressing transgenic mice is normal, but that injury responses are altered. Immunohistochemical analysis employing appropriate markers will be used to determine the effect of FGF2 absence or overexpression on neuronal survival, axonal sprouting and glial reactivity in normal and injured mouse hippocampus. Aim 4: To test whether FGF2 regulates the expression of proteins that are involved in promoting plasticity and repair. The effect of FGF2 knockout and over-expression on the levels of neurotrophins, cytokines and chemokines will be determined. Aim 5: To test whether FGF2 is important in the normal maintenance of the aging CNS. The volume of hippocampus, neuronal and glial numbers, and cytoarchitecture of hippocampus of old FGF2 knockout and FGF-2 overexpressing mice will be determined.