GROWTH FACTORS IN THE ADULT AND AGING BRAIN

在过去的十年中，人们已经认识到，一种常见的病理性 在影响老年人的疾病中观察到的异常， 因为阿尔茨海默氏症或帕金森氏症是神经元过早退化。 此外，已经证明存在特定因素， 负责开发，维护和生存的特定 神经元群体。 因此，有人建议， 或神经退行性疾病过程的进展可能是由于 特定营养因子的不可利用性。 由于帕金森病是 以中脑多巴胺的加速退化为特征 神经元，我们一直从事研究，确定营养因子， 能够提高多巴胺神经元的存活率。 我们发现 表皮生长因子（EGF）及其结构和功能类似物， 转化生长因子-α（TGF-α），能够增加 体外发育中多巴胺神经元的存活。 我们和其他人已经 EGF和TGF-α在多巴胺能神经元中表达的证据 成熟动物的投射部位。 最近的研究表明， EGF给药的动物，其中多巴胺能黑质纹状体 通路被切断，能够增加多巴胺能神经元的数量， 纤维 这些结果表明，EGF可能具有营养作用， 成熟动物的多巴胺神经元缺乏这种生长因子 会导致多巴胺神经元的退化 其他实验室 已经证明碱性成纤维细胞生长因子（bFGF）和脑 衍生神经营养因子（BDNF）也可以提供营养支持 发育中的多巴胺神经元和成熟的 动物 因此，我们建议研究基因表达的调控 在正常大脑发育过程中， 成熟，与发生在大脑中的神经变性有关， 韦弗突变小鼠和响应MPTP毒性范例，其中 多巴胺神经元的恢复能力各不相同 以确定是否 中纹状体相对于中脑边缘的选择性脆弱性 多巴胺神经元可以用不同的营养需求来解释， 建议中的研究旨在确定， 杂交，如果在多巴胺神经元之间存在差异， 黑质和腹侧被盖区的表达， 生长因子受体 预计这种解剖学和 定量检测这些假定的多巴胺能神经元的表达， 生长因子及其各自的受体在正常和 神经退化的大脑应该有助于表征特定的 这些肽在多巴胺营养支持中的生理功能 神经元

During the past decade, it has been recognized that one common pathologic abnormality that has been observed in diseases that effect the elderly such as Alzheimer's or Parkinson's disease is premature neuronal degeneration. Further, it has been demonstrated that specific factors exist which are responsible for the development, maintenance, and survival of specific neuronal populations. It has therefore been suggested that the induction or progression of a neurodegenerative disease process may be due to the unavailability of a specific trophic factor. Since Parkinson's disease is characterized by the accelerated degeneration of mesencephalic dopamine neurons, we have been engaged in studies identifying trophic factors which are able to enhance the survival of dopamine neurons. We have found that epidermal growth factor (EGF) and its structural and functional analog, transforming growth factor-alpha (TGF-alpha), are able to increase the survival of developing dopamine neurons in vitro. We and others have evidence that both EGF and TGF-alpha are expressed in dopaminergic projection sites in mature animals. It has recently been demonstrated that EGF administration to animals, in which the dopaminergic nigrostriatal pathway has been transected, is able to increase the number of dopaminergic fibers. These results suggest that EGF may have trophic effects on dopamine neurons in mature animals and that lack of this growth factor could result in the degeneration of dopamine neurons. Other laboratories have demonstrated that basic fibroblast growth factor (bFGF) and brain derived neurotrophic factor (BDNF) can also able to provide trophic support to developing dopamine neurons and to lesioned dopamine neurons in mature animals. Therefore we propose to study the regulation of gene expression of each of these growth factor mRNAs in the course of normal brain maturation, in association with the neurodegeneration that occurs in the weaver mutant mouse and in response to MPTP toxicity paradigms where dopamine neurons vary in the ability to recover. In order to determine if the selective vulnerability of the mesostriatal versus the mesolimbic dopamine neurons could be explained by different trophic requirements, studies in the proposal are designed to determine, by in situ hybridization, if there are differences between dopamine neurons in the substantia nigra and ventral tegmental area in their expression of these growth factor receptors. It is anticipated that this anatomical and quantitative examination of the expression of these putative dopaminergic growth factors and their respective receptors in normal and neurodegenerating brains should aid in the characterization of the specific physiologic functions for these peptides in the trophic support of dopamine neurons.