IMPROVING DOPAMINE CELL SURVIVAL AFTER NEURAL TRANSPLANT

描述：在过去的15年里，在 胚胎多巴胺细胞移植在动物体内的研究。这些 实验已经导致神经移植作为一种正在开发的治疗方法 患有晚期帕金森氏症的人类。几乎每一条原则 在老鼠身上建立的已被证明适用于人类。RATS已定义 适合移植的发育阶段，并证明 只有在突起生长和神经再支配之后，行为效应才会发生 纹状体的。人类已成为存活时间最长的物种 移植。尽管取得了如此显著的进步，但移植并没有 治愈了人类或实验动物的帕金森综合症。在……里面 动物习得行为的恢复一直难以实现。 多巴胺细胞存活率低和神经突起生长有限是 神经移植的主要缺点。低至5%至10%的 多巴胺细胞存活下来。为了改善神经移植， PI已经制定了减少多巴胺细胞死亡的策略 体外培养。在之前的实验中，他们已经证明了类胰岛素 生长因子(IGF-1)、碱性成纤维细胞生长因子(BFGF)和胶质细胞 衍生神经营养因子(GDNF)具有相加促进作用 多巴胺细胞在体外存活。PI已经证明了改进的 生存是细胞程序性死亡的结果。在……里面 在老年猴子的实验中，我们发现多巴胺细胞存活 比年轻动物的情况要糟糕得多。在这项拨款提案中，我们将 试图通过一种系统的方法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：细胞凋亡 神经移植后前14天的细胞程序性死亡 将是青少年(10岁)多巴胺细胞死亡的主要原因 至12周龄)和老年(18月龄)雄性Fisher 344只。 假设二：长期细胞存活(3个月)将变得不那么好 在老年动物中，比在幼年动物中。假设III：胚胎 纹状体联合移植或转基因细胞联合移植 为了产生生长因子IGF-1、bFGF和GDNF将会得到改善 多巴胺细胞在早期(1-14天)和晚期(3个月)的存活 移植后的次数。如果长期存活率相对较低 研究人员预计，在老年动物中进行多巴胺细胞移植 生长因子或纹状体联合移植会有相对 在老年动物中比在幼年动物中更有价值。如果这些实验是 成功的类似策略可以直接推广到人类身上 接受胚胎多巴胺神经移植治疗帕金森氏症。

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.