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: 6267631
• 负责人: AYALLA BARNEA
• 金额: $ 15.67万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-15 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6267631
• 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 引发和发展的分子机制 大脑中的神经元死亡，特别是在阿尔茨海默氏症的大脑中， 患者本试验研究的目的是建立一个文化研究 来自“正常”人类流产和唐氏综合征的胎儿脑细胞 综合征（DS）。这些文化将作为研究 导致阿尔茨海默病中神经元死亡的过程。合理 选择DS大脑是基于一致的发现， 阿尔茨海默病患者的神经病理学发展在更早的年龄比 “正常”的老年人，并假设过程导致 阿尔茨海默病神经病理学在比“正常”老年人更早的年龄 并假设导致阿尔茨海默病神经病理学的过程 在更早的时候就开始运作了，甚至可能在胎儿时期就已经开始运作了。 S.A.1.建立人体模型系统，用于研究 神经元存活由神经元和神经胶质细胞组成的聚集培养物 将从大脑皮层分离的脑细胞中建立 “正常的”人类流产和DS大脑，使用我们以前的 用这种来自大鼠胎脑的培养系统作为 指导方针。两种肽能神经元，神经肽Y（NPY） 和生长抑素（SRIF），将作为模型神经元。形态 这些神经元的功能分化和地形 将定义单元的布置。 S.A.2.验证我们的碱性成纤维细胞生长因子的“乒乓”假说 （bFGF）-β-淀粉样蛋白相互作用。神经突发芽与 老年斑形成的早期阶段我们 工作“乒乓”假说是bFGF刺激表达， 编码β-淀粉样前体蛋白（APP）的基因，APP是一种产物 这反过来又刺激更多的bFGF产生。因此，每轮bFGF - β-淀粉样蛋白相互作用导致细胞外 能够促进神经突发芽的药物，其中β-淀粉样蛋白可以 成为一个重要的组成部分。我们将首先评估 碱性成纤维细胞生长因子对大鼠海马神经肽Y/SRIF神经元突起生长和存活的影响 我们的人类模型系统。这些结果将作为基础， 全面的研究建议，以阐明细胞和细胞内 过程中bFGF -β-淀粉样蛋白相互作用的机制 导致神经元死亡。