MANIPULATION OF BASAL GANGLIA AGING BY DIET AND DOPAMINE

这项研究将考察啮齿动物基底节衰老的处理方法。 重点研究了一种中间体GFAP的转录变化 星形胶质细胞的细丝，显示出在 衰老。除GFAP外，其他反映衰老的星形胶质细胞标志物(apoE和apoJ) 也增加了对损伤的反应，这表明了假设 一些自发的衰老变化代表了星形胶质细胞对 与对病变的急性反应相同的刺激。作为一个理由， 这些关于控制衰老、慢性饮食限制(DR)的研究 减少与年龄相关的纹状体多巴胺能D2受体的丢失，而 多巴胺激动剂培高利特(PERG)减少黑质纹状体的丢失 终点站。此外，DR抑制星形胶质细胞的增龄性增加 纹状体中的GFAP mRNA(初步数据)，正如我们在 海马体和下丘脑。我们假设操控衰老 在慢性DR或PERG所致的基底节区，共有共同的机制 减轻氧化损伤，刺激神经胶质细胞过度活跃。在……里面 特别是，我们将研究DR和PERG如何影响神经胶质细胞的年龄变化 为了检验激活的小胶质细胞增加细胞因子产生的假设 转化生长因子-β1和其他细胞因子进而激活星形胶质细胞 增加GFAP和apoJ(聚集素)的产量。我们还将检查 D2受体信使核糖核酸，一种随着年龄增长而减少的神经元标记物。 氧化损伤将直接在蛋白质和脂类中进行检测。我们 还将研究GFAP对 损伤和衰老。这些研究探讨了基底节的发病机制 在正常衰老过程中运动功能发生变化的衰老 可能增加实质灾难性损失风险的变化 导致帕金森病(PD)的黑质神经元。

This study will examine manipulations of basal ganglia aging in rodents with an emphasis on transcriptional changes in GFAP, an intermediate filament of astrocytes that shows a general increase in prevalence during aging. Besides GFAP, other astrocyte markers of aging (apoE and apoJ) also increase in response to lesioning, which suggests the hypothesis that some spontaneous aging changes represent responses of astrocytes to the same stimuli as in acute responses to lesions. As a rationale for these studies on the manipulation of aging, chronic diet restriction (DR) reduced the age-related loss of striatal dopaminergic D2-receptors, while the DA agonist pergolide (PERG) reduced the loss of nigrostriatal terminals. Moreover, DR attenuated age-related increase of astrocyte GFAP mRNA in the striatum (preliminary data), as we have found in hippocampus and hypothalamus. We hypothesize that manipulation of aging in the basal ganglia by chronic DR or PERG share common mechanisms by attenuating oxidative damage that stimulates glial hyperactivity. In particular, we will examine how DR and PERG influence age changes in glia to test the hypothesis that activated microglia increase production of TGF-Beta1 and other cytokines that, in turn, activate astrocytes to increase production of GFAP and apoJ (clusterin). We will also examine the D2-receptor mRNA, a neuronal marker which decreases during aging. Oxidative damage will be directly assayed in proteins and lipids. We will also examine transcriptional mechanisms in the responses of GFAP to lesions and aging. These studies probe mechanisms in basal gangliar aging that bear on changes in motor functions during normal aging and changes that may increase the risk of catastrophic loss of substantia nigra neurons that lead to Parkinson disease (PD).