SITE OF GRAFT PLACEMENT IN HOST

宿主体内的移植部位

• 批准号: 6112266
• 负责人: Jane R Taylor
• 金额: $ 20.03万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112266
• 关键词: Cercopithecidae; Parkinson's disease; behavior; behavior test; brain mapping; caudate nucleus; cerebellum; corpus striatum; dopamine; methylphenyltetrahydropyridine; nervous system transplantation; neurotrophic factors; psychomotor function; putamen; substantia nigra

Pre-clinical studies of the neural mechanisms of motor function suggest that there may be regionally specific sites advantageous for intracerebral neural graft placement into the host. One site, the substantia nigra, ultimately might prove to be the most advantageous due tot he possible restoration of natural neural circuits. Clinical studies have begun which claim superiority of one placement site over another, particularly the putamen over the caudate, without any comparative studies in primates. This project will study the effectiveness of various graft placements in order to understand the site-dependency of functional improvements in parkinsonian behavior after grafting. Monkeys with stable MPTP-induced parkinsonism will be used exclusively in this project for functional studies. A battery of behavioral test will assess the extent and nature of functional changes. Spontaneous behavior will be used to assess the general status of the subject, and tests that examine cognitive and sensorimotor function will be used to determine the effectiveness of grafts on specific functional deficits. The specific experiments will compare placements in the caudate with placements into the putamen. Control comparisons will include cannula placement sham surgeries, cerebellar tissue grafts, and unilateral substantia nigra grafts into each structure. Since multiple small grafts might innervate the entire striatum better than a confined graft of equal volume, we will test this possibility. In addition, grafts into anatomically defined subregions of the striatum may result in selective improvements in specific behavior(s) or types of improvements measured by performance on different tasks or aspects of tasks that are dependent on striatal dopamine or the integrity of frontocaudate circuitry. Some preliminary studies have suggested simple vs complex behavior, or indeed motor vs cognitive behavior, may be affected differentially by the placements of grafts into subregions of the large and heterogenous caudate. If experiments using growth factors or co-grafts further support the possibility and demonstrate suitable methods, we will also examine whether grafts of fetal SN into the SN or bridge grafts from the SN to the striatum would produce some additional functional improvements particularly in behavior dependent on external afferent inputs impinging on the SN rather than tonic terminal increases in dopamine in the MPTP denervated striatum. The general methods, experimental design outlines and assessment measures are presented separately in detail in each of the Core sections. Transplantation methods as developed and standardized by the program will be utilized in these studies and maintained consistently to provide proper controls for the principal variable of interest -- distribution of grafts within the host. This project may provide data important for understanding how graft placement affects the various behavioral functions of the nigrostriatal dopamine system and more rational ways to ameliorate deficits in dopamine system function which may be of clinical relevance.

运动功能神经机制的临床前研究表明 可能有特定于区域特定的站点对脑内有利 神经移植物放入宿主。 一个地点，底底尼格拉， 最终可能被证明是最有利的 恢复天然神经回路。 临床研究已经开始 声称一个安置地点优于另一个位置，尤其是 在尾状的梭子上没有任何比较研究。 该项目将研究各种移植位置的有效性 为了了解功能改进的站点依赖性 嫁接后的帕金森氏症行为。 具有稳定的MPTP引起的帕金森主义的猴子将专门用于 这个功能研究项目。 一系列行为测试将 评估功能变化的程度和性质。 自发行为 将用于评估主题的一般状况，并测试 检查认知和感觉运动功能将用于确定 移植物对特定功能缺陷的有效性。 具体 实验将比较尾矿中的位置与放置位置 鬼盘。 控制比较将包括套管放置假 手术，小脑组织移植物和单侧底底nigra移植物 进入每个结构。 由于多个小移植物可能会影响 整个纹状体比同等体积的受限移植物更好，我们将测试 这种可能性。 另外，移植物进入解剖学定义的子区域 纹状体可能会导致特定的选择性改善 行为或通过表现衡量的改进类型 依赖纹状体多巴胺或 额动物电路的完整性。 一些初步研究 建议简单与复杂行为，或者确实是电动机与认知 行为可能会受到移植物的位置的影响 大型和异质尾状的子区域。 如果使用生长因子或共枝的实验进一步支持 可能性并证明合适的方法，我们还将检查是否是否 胎儿SN的移植物进入SN或桥接移植物从SN到纹状体 会产生一些其他功能改进，特别是在 行为取决于影响SN的外部传入输入 比强直末端增加了MPTP纹状体中多巴胺的增加。 一般方法，实验设计概述和评估措施 在每个核心部分中分别详细介绍。 该程序开发和标准化的移植方法将 在这些研究中使用并始终保持以提供适当的 关注的主变量的控制 - 移植物的分布 主机内。 该项目可能为了解移植物如何提供重要的数据 放置会影响斑道纹状体的各种行为函数 多巴胺系统和更合理的方法来改善多巴胺的缺陷 可能与临床相关的系统功能。