GROWTH FACTORS IN THE ADULT AND AGING BRAIN

在过去的十年里，人们已经认识到一种常见的病理 在影响老年人的疾病中观察到的异常现象 因为阿尔茨海默氏症或帕金森氏症是早产儿的神经元退化。 此外，已经证明存在特定的因素，这些因素是 负责特定项目的开发、维护和生存 神经元群。因此，有人提出，归纳 或神经退行性疾病过程的进展可能是由于 无法获得特定的营养因子。因为帕金森氏症 以中脑多巴胺加速变性为特征 神经元，我们一直在进行识别营养因子的研究 能够提高多巴胺神经元的存活率。我们发现， 表皮生长因子及其结构和功能类似物， 转化生长因子-α(转化生长因子-α)能够增加 发育中的多巴胺神经元在体外的存活。我们和其他人有 证据表明EGF和转化生长因子-α在多巴胺能神经元中均有表达 成熟动物的投射部位。最近已经证明， EGF对动物的作用，其中多巴胺能黑质纹状体 通路已经被横断，是能够增加多巴胺能 纤维。这些结果表明，EGF可能具有营养作用。 成熟动物中的多巴胺神经元以及这种生长因子的缺乏 可能导致多巴胺神经元退化。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)也能提供营养支持 对发育中的多巴胺神经元和成熟时受损的多巴胺神经元 动物。因此，我们建议研究基因表达的调控。 这些生长因子在正常大脑过程中的mRNAs 成熟，与神经退行性变有关，发生在 Weaver突变小鼠及对MPTP毒性的响应范式 多巴胺神经元的恢复能力各不相同。为了确定是否 中纹状体与边缘中叶的选择性易损性 多巴胺神经元可以用不同的营养需求来解释， 提案中的研究旨在通过现场确定 杂交，如果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。预计这一解剖结构和 这些可能的多巴胺能神经元表达的定量检测 正常人和正常人的生长因子及其相应的受体 神经退行性变的大脑应该有助于表征特定的 这些多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.