ROLE FOR FIBROBLAST GROWTH FACTOR IN ALZHEIMER'S DISEASE

成纤维细胞生长因子在阿尔茨海默病中的作用

• 批准号: 6098586
• 负责人: AYALLA BARNEA
• 金额: $ 15.74万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098586
• 关键词: Alzheimer's disease; Downs syndrome; amyloid proteins; cell cell interaction; cerebral cortex; disease /disorder model; embryo /fetus tissue /cell culture; fibroblast growth factor; glia; human tissue; immunocytochemistry; intermolecular interaction; mixed tissue /cell culture; model design /development; neural degeneration; neuritic plaques; neuronal guidance; neurons; neuropeptide Y; neuropharmacology; somatostatin

Our long-term objective is to gain insight into the cellular and molecular mechanisms underlying the initiation and progression of neuronal death in the brain, particularly in brains of Alzheimer patients. The goal of this pilot study is to establish a culture study of fetal brain cells derived from "normal" human abortuses and from Down Syndrome (DS). These cultures will serve as models for the study of processes leading to neuronal death in Alzheimer disease. The rational for choosing the DS brain is based on the consistent findings that DS patients develop Alzheimer neuropathology at a much earlier age than "normal" aging people and on the hypothesis that processes leading to Alzheimer neuropathology at a much earlier age than "normal" aging people and on the hypothesis that processes leading to Alzheimer neuropathology are operative at an earlier age, possibly already even in the fetus. S.A.1. Establish a human model system for the study of the regulation of neuronal survival Aggregate cultures comprised of neurons and glial cells will be established from dissociated brain cells obtained from the cortex of "normal" human abortuses and of DS brains, using our previous experience with this culture system derived from rat fetal brains as a guideline. Two population of peptidergic neurons, neuropeptide Y (NPY) and somatostain (SRIF), will serve as model neurons. The morphological and functional differentiation of these neurons and the topographical arrangement of the cells will be defined. S.A.2. Test our "ping pong" hypothesis of basic fibroblast growth factor (bFGF) - Beta-amyloid interactions. Neurite sprouting has been implicated in the early stages of senile plaque formation in Alzheimer disease. Our working "ping pong" hypothesis is that bFGF stimulates expression of the gene encoding Beta-amyloid precursor protein (APP), a product(s) of which, in turn, stimulates more bFGF production. Thus, each round of bFGF - Beta-amyloid interaction results in greater extracellular levels of agents capable of promoting neurite sprouting, of which Beta-amyloid may be a substantial component. We will initiate this study by assessing the effect of bFGF on neurite sprouting and survival of NPY/SRIF neurons in our human model systems. These results will serve as the basis for a full-scale research proposal to elucidate the cellular and intracellular mechanisms underlying bFGF - Beta-amyloid interactions in processes leading to neuronal death.

我们的长期目标是深入了解细胞和 骨肉瘤发生和发展的分子机制 大脑中的神经元死亡，特别是阿尔茨海默病患者的大脑 病人。这项先导研究的目标是建立一项文化研究 取自“正常”人流产儿的胎儿脑细胞 综合征(DS)。这些文化将成为研究 阿尔茨海默病中导致神经元死亡的过程。理性的人 因为选择DS大脑是基于一致的发现DS 患者出现阿尔茨海默病神经病理的年龄比 “正常”老龄化的人和导致衰老的过程 阿尔茨海默氏症的神经病理表现比“正常”老年人早得多 以及关于导致阿尔茨海默病神经病理的过程的假说 在较小的年龄就可以手术，甚至可能在胎儿时期就已经开始了。 S.A.1。建立调控研究的人体模型体系 由神经元和神经胶质细胞组成的神经元存活聚集体培养 将从大脑皮层分离的脑细胞中建立 “正常”的人类流产和DS脑，使用我们以前的 从大鼠胎脑中提取的这种培养系统作为一种 指导方针。神经肽Y(NPY)是两类肽能神经元 和生长抑素(SRIF)，将作为模型神经元。形态上的 这些神经元的功能分化和地形图 将定义单元格的排列。 S.A.2。测试我们关于碱性成纤维细胞生长因子的“乒乓球”假说 (碱性成纤维细胞生长因子)-β-淀粉样蛋白相互作用。已经牵涉到轴突的萌发 在阿尔茨海默病的老年斑形成的早期阶段。我们的 “乒乓球”假说认为碱性成纤维细胞生长因子刺激血管内皮细胞的表达 编码β-淀粉样前体蛋白(APP)的基因，其产物(S) 这反过来又会刺激更多碱性成纤维细胞生长因子的产生。因此，每一轮bFGF. -β-淀粉样蛋白相互作用导致更高的细胞外水平 能够促进轴突萌发的药物，其中β-淀粉样蛋白可能 成为一个重要的组成部分。我们将在启动这项研究时，评估 碱性成纤维细胞生长因子对大鼠脑内NPY/SRIF神经元突起生长和存活的影响 我们的人体模型系统。这些结果将作为一项 全面研究建议，以阐明细胞和细胞内 碱性成纤维细胞生长因子-β-淀粉样蛋白相互作用的机制 导致神经元死亡。