AGING AND DOPAMINE GRAFTS IN PARKINSONIAN MONKEYS

帕金森病猴的衰老和多巴胺移植

• 批准号: 6372380
• 负责人: Timothy J. Collier
• 金额: $ 72.9万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6372380
• 关键词: Macaca mulatta; Parkinson's disease; age difference; angiogenesis; apoptosis; basal ganglia; denervation; dopamine; dopamine receptor; embryo /fetus tissue transplantation; experimental brain lesion; homologous transplantation; juvenile animal; mature animal; mesencephalon; methylphenyltetrahydropyridine; necrosis; neurons; neurotrophic factors; nonhuman therapy evaluation; oxidative stress; prognosis; receptor binding

DESCRIPTION: (Verbatim from the Applicant's Abstract) Transplantation of embryonic dopamine (DA) neurons as an experimental therapy for Parkinson's disease (PD) is currently under evaluation. The non-human primate treated with the neurotoxin MPTP has served as an important animal model for the disease and the grafting paradigm, and has had significant predictive value for results of early clinical trials. Despite some encouraging clinical findings, relative survival of grafted DA neurons is low and improvement of behavioral symptoms is incomplete. Part of the disparity between results in animals and PD patients may relate to failure of animal studies to model certain characteristics of potential recipients of graft therapy that impact significantly on the environment of grafted cells. One characteristic of this patient population that can be examined in animals is the influence of chronological age of the transplant recipient. The interactions between age-related changes inherent to this system in graft recipients, the response of the aging system to accelerated loss of nigral DA neurons, and the impact these changes have on the environment for grafted tissue only recently have received attention. We have found that the viability and function of grafted DA neurons is profoundly diminished in DA-depleted aged rats. In addition, these aged animals exhibit important deficits in compensatory responses to DA depletion including decreased striatal neurotrophic activity. Recent clinical results also suggest diminished graft efficacy in elderly patients. Advancing chronological age of the transplant recipient may represent a previously under-appreciated risk of diminished graft viability and function that may mandate study of novel grafting strategies 1 to achieve good therapeutic results. It is the goal of this proposal to evaluate the influence of chronological age of the host on graft viability and function in MM?-treated non-human primates. Tissue from single donors will be divided for implantation into pairs of young adult and aged hemiparkinsonian monkeys, with behavioral, mophological, and biochemical techniques employed to study rates of apoptosis in grafts, survivai, neurite outgrowth and release of DA from grafted cells, and receptor, metabolic and -trophic responses in the host. Additional analyses will examine aging-related changes in microvasculature and oxidative stress in the graft environment. These studies will provide valuable information on the response of the aged brain to accelerated DA neuron loss, the interaction between aging in the host and graft viability, indicate mechanisms of intervention with graft survival and function in the aged brain, and will aid in matching patients with the optimal therapeutic approach.

描述：（逐字从申请人的摘要中）移植 胚胎多巴胺（DA）神经元作为帕金森氏症的实验疗法 疾病（PD）目前正在评估中。接受过的非人类灵长类动物 神经毒素MPTP已成为该疾病的重要动物模型， 嫁接范式，并且具有显着的预测价值 早期临床试验。尽管有一些令人鼓舞的临床发现，但相对 接枝DA神经元的生存率很低，行为症状的改善为 不完整。动物和PD患者的结果之间的部分差异 可能与动物研究未能建模的某些特征有关 潜在的移植疗法受到重大影响的接枝疗法 移植细胞的环境。该患者人群的一个特征 可以在动物中检查的是年龄的影响 移植接受者。与年龄相关的变化之间固有的固有的相互作用 该系统在接收者中，老化系统对 加速nigral da神经元的丧失，这些变化对 移植组织的环境仅最近才受到关注。我们有 发现接枝DA神经元的生存能力和功能是深刻的 减少了DA耗尽的老年大鼠。另外，这些老年动物表现出 对DA耗竭的补偿性反应的重要缺陷，包括 纹状体神经营养活性降低。最近的临床结果也表明 老年患者的移植功效降低。促进年龄的年龄 移植接收者可以代表以前未被告顾的风险 移植的生存力和功能降低，可能会授权新的研究 嫁接策略1以获得良好的治疗结果。这是目标 这项提出评估宿主按年龄的影响的建议 mm？处理过的非人类灵长类动物的移植活力和功能。组织来自 单个捐助者将被划分为成对成年成年成年和 陈年的半镇猴，具有行为，乳清学和生化的猴子 用于研究移植物凋亡率的技术 从移植细胞以及受体，代谢和 - 宿主中的四光反应。其他分析将检查与衰老有关的 在移植环境中微举行和氧化应激的变化。 这些研究将提供有关老年人响应的宝贵信息 大脑加速DA神经元丧失，宿主衰老之间的相互作用 和移植生存力，指示移植物存活的干预机制 并在老年大脑中发挥作用，并将有助于与患者相匹配 最佳治疗方法。