IMPROVING DOPAMINE CELL SURVIVAL AFTER NEURAL TRANSPLANT

提高神经移植后多巴胺细胞的存活率

• 批准号: 2379588
• 负责人: CURT R FREED
• 金额: $ 19.22万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-15 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2379588
• 关键词: Parkinson's disease; adenosine; age difference; apoptosis; cell transplantation; disease /disorder model; dopamine; embryo /fetus cell /tissue; fibroblast growth factor; growth factor; insulinlike growth factor; laboratory rat; nervous system regeneration; nervous system transplantation; neural transmission; neurophysiology; neurotransmitter metabolism; tissue /cell culture

DESCRIPTION: The past 15 years have seen substantial progress in research on embryonic dopamine cell transplantation in animals. These experiments have led to neurotransplantation as a developing therapy for humans with advanced Parkinson's disease. Nearly every principle established in the rat has proven applicable to humans. Rats defined the developmental stage suitable for transplant and demonstrated that behavioral effects occur only after process outgrowth and reinnervation of the striatum. Man has become the species with the longest surviving transplants. Despite this remarkable progress, transplants have not cured Parkinsonian syndromes in man or experimental animals. In animals, restoration of learned behaviors has been difficult to achieve. Poor survival of dopamine cells and limited neurite outgrowth are the major shortcomings of neurotransplantation. As few as 5% to 10% of dopamine cells survive. In an attempt to improve neural transplantation, the PI has developed strategies for reducing dopamine cell death in vitro. In previous experiments, they have shown that insulin-like growth factor (IGF-1), basic fibroblast growth factor (bFGF), and glial derived neurotropic factor (GDNF) have additive effects for promoting dopamine cell survival in vitro. The PI has demonstrated that improved survival is the result of apoptotic programmed cell death. In experiments in aged monkeys, we have found that dopamine cell survival is much worse than in younger animals. In this grant proposal we will try to improve transplants in young and aged rats through a systemic study of cell survival after transplant. Hypothesis I: Apoptotic programmed cell death in the first 14 days after neural transplantation will account for the majority of dopamine cell death in both young (10 to 12 weeks of age) and old (18 months) male Fisher 344 rats. Hypothesis II: Long term cell survival, (3 months), will be less good in aged animals than in young animals. Hypothesis III: Embryonic striatal cotransplants or cotransplants of cells genetically modified to produce the growth factors IGF-1, bFGF, and GDNF will improve dopamine cell survival both in early (1-14 days) and late (3 months) times after transplant. If there is relatively poor long term survival of dopamine cell transplants in aged animals, the investigators expect that growth factors or striatal cotransplants will have relatively greater value in aged than in young animals. If these experiments are successful, similar strategies could be directly extended to humans receiving embryonic dopamine neurotransplants for Parkinsons' disease.

说明：过去15年来， 动物胚胎多巴胺细胞移植的研究。 这些 实验已经导致神经移植作为一种发展中的治疗方法， 患有晚期帕金森病的人。 几乎所有的原则 在大鼠中建立的模型已被证明适用于人类。 大鼠定义 适合移植发育阶段，并证明， 行为效应只发生在过程生长和神经再支配之后 纹状体。 人类已成为世界上生存时间最长的物种 移植 尽管取得了显著的进步，但移植并没有 在人类或实验动物中治愈帕金森综合征。 在 在动物中，学习行为的恢复是很难实现的。 多巴胺细胞的存活率低和有限的神经突生长是 神经移植的主要缺点 只有5%到10%的 多巴胺细胞存活。 为了改善神经移植， PI已经开发出减少多巴胺细胞死亡的策略， 体外 在以前的实验中，他们已经表明， 生长因子（IGF-1）、碱性成纤维细胞生长因子（bFGF）和神经胶质细胞生长因子（GFAP）。 衍生的神经营养因子（GDNF）具有促进 体外多巴胺细胞存活率。 PI已经证明， 存活是细胞凋亡程序性死亡的结果。 在 在老年猴子的实验中，我们发现多巴胺细胞存活 比年轻的动物更糟糕。 在这份赠款提案中，我们将 试图通过系统的方法来改善年轻和老年大鼠的移植， 移植后细胞存活的研究。 假设一：凋亡 神经移植后14天内的程序性细胞死亡 将占大多数的多巴胺细胞死亡，在这两个年轻人（10 至12周龄）和老年（18个月）雄性Fisher 344大鼠。 假设二：长期细胞存活（3个月），将不太好 而不是年轻的动物。 假设三：胚胎 纹状体共移植物或遗传修饰的细胞的共移植物 产生生长因子IGF-1、bFGF和GDNF将提高 早期（1-14天）和晚期（3个月）的多巴胺细胞存活率 移植后的时间 如果长期生存率相对较差， 研究人员预计， 生长因子或纹状体共同移植物相对来说 老年动物比年轻动物更有价值。 如果这些实验 成功的类似策略可以直接推广到人类 接受胚胎多巴胺神经移植治疗帕金森病