GROWTH FACTORS IN THE ADULT AND AGING BRAIN

成人和衰老大脑中的生长因子

基本信息

批准号：
3120229
负责人：
MARIANN M BLUM
金额：
$ 10.73万
依托单位：
MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-05-01 至 1995-04-30
项目状态：
已结题

项目摘要

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.

在过去的十年中，人们已经认识到一种常见的病理学在影响老年人的疾病中观察到的异常，例如阿尔茨海默病或帕金森病是神经元过早变性。此外，已经证明存在特定因素：负责特定的开发、维护和生存神经元群。因此有人建议采用归纳法神经退行性疾病过程或进展可能是由于特定营养因子的缺乏。由于帕金森病是以中脑多巴胺加速退化为特征神经元，我们一直致力于识别营养因子的研究能够增强多巴胺神经元的存活。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的多巴胺神经元的存活。我们和其他人有有证据表明 EGF 和 TGF-α 均在多巴胺能细胞中表达成熟动物的投射部位。最近已经证明给动物施用EGF，其中多巴胺能黑质纹状体通路被横断，能够增加多巴胺能的数量纤维。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以及缺乏这种生长因子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）也能提供营养支持发育中的多巴胺神经元和成熟中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 mRNA 在正常大脑发育过程中的每一个成熟，与发生在的神经变性有关 weaver 突变小鼠和对 MPTP 毒性范例的响应，其中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中边缘的选择性脆弱性多巴胺神经元可以通过不同的营养需求来解释，该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在表达这些生长因子受体。预计这种解剖学和对这些假定的多巴胺能的表达进行定量检查生长因子及其各自的受体在正常和神经退行性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。