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（FGF 2）是一种有效的促分裂原和神经营养因子。成熟的CNS 这个因子的含量高得惊人FGF 2缺乏 疏水信号肽序列，并且不能有效地从 未受刺激的健康细胞我们的假设是， FGF 2的释放，导致广泛表达的 跨膜FGF受体（FGFR）。这一假设表明， FGF 2在神经系统中的主要作用是作为早期的神经元， 细胞损伤信号和启动损伤反应，包括神经胶质细胞 激活和神经元可塑性。以下具体目标将 测试所提出的FGF 2作用的生理模型： 目的1：测试损伤是否将FGF 2释放到细胞外空间 并激活FGF受体。正常人外周血细胞外FGF-2水平 和损伤的CNS将使用高度敏感的FGF 2在体内定量。 比色法 还将测量损伤后的FGF受体活化。 目的2：测试是否是简单的质膜破裂或额外的 特定的输出机制导致损伤后FGF 2的释放。FGF2 释放机制将在星形胶质细胞培养物中表征。 目的3：检测FGF 2基因敲除是否影响海马细胞结构 而FGF 2过表达转基因小鼠是正常的， 反应被改变了。免疫组织化学分析， 将使用适当的标记物来确定FGF 2缺失的影响 或过度表达对神经元存活、轴突发芽和神经胶质细胞增殖的影响。 正常和损伤的小鼠海马的反应性。 目的4：检测FGF 2是否调节蛋白质的表达， 参与促进可塑性和修复。FGF 2的作用 在神经营养因子、细胞因子水平上的敲除和过表达 和趋化因子。 目的5：检测FGF 2在正常维持细胞增殖中是否重要。 衰老的中枢神经系统海马体积，神经元和胶质细胞数量， FGF-2基因敲除和FGF-2基因敲除对海马神经元细胞结构的影响 将确定过表达小鼠。

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.