AGING AND DOPAMINE GRAFTS IN PARKINSONIAN MONKEYS

描述：（逐字来自申请人的摘要） 胚胎多巴胺（DA）神经元作为帕金森氏症的实验性治疗 疾病（PD）目前正在评估中。非人类灵长类动物接受了 神经毒素MPTP已经作为该疾病的重要动物模型， 嫁接范例，并已具有显着的预测价值的结果， 早期临床试验尽管有一些令人鼓舞的临床研究结果， 移植的DA神经元的存活率低， 不完整动物和PD患者结果之间的部分差异 可能与动物研究未能模拟某些特征有关， 移植治疗的潜在接受者， 移植细胞的环境。这个病人群体的一个特点是 可以在动物中检查的是实际年龄的影响， 移植受体与年龄相关的变化之间的相互作用， 这个系统在移植受体，老化系统的反应， 黑质DA神经元的加速损失，以及这些变化对 移植组织的环境最近才受到关注。我们有 发现移植的DA神经元的活力和功能是深刻的 在DA耗尽的老年大鼠中减少。此外，这些老年动物还表现出 对DA耗竭的代偿反应的重要缺陷，包括 纹状体神经营养活性降低。最近的临床结果也表明 降低老年患者的移植物疗效。年龄增长 移植受体可能代表了先前未被充分认识的风险， 移植物活力和功能降低，可能需要研究新的 嫁接策略1，以达到良好的治疗效果。它的目标是 这一建议，以评估的影响，实足年龄的主机 MM中的移植物活性和功能？治疗过的非人类灵长类动物组织从 单个供体将被分成成对的年轻成年人进行植入， 老年偏侧帕金森病猴，具有行为、形态学和生化 用于研究移植物、存活、神经突中细胞凋亡率的技术 DA从移植细胞中的生长和释放，以及受体、代谢和 - 宿主的营养反应。其他分析将检查与年龄相关的 移植物环境中微血管和氧化应激的变化。 这些研究将为老年人的反应提供宝贵的信息 大脑加速DA能神经元的丢失，在宿主衰老的相互作用 和移植物活力，表明干预移植物存活的机制 并在老年大脑中发挥作用，并将有助于将患者与 最佳治疗方法

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.