Primate Model of Stroke and Recovery in Aging

灵长类动物中风和衰老恢复模型

基本信息

批准号：
7669208
负责人：
TARA L MOORE
金额：
$ 17.27万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-15 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7669208
关键词：
Affect Age Aging American Heart Association Animal Model Animal Testing Animals Area Behavioral Blood Vessels Boxing Brain Centers for Disease Control and Prevention (U.S.)Contralateral Data Development Digit structure Disease Electrophysiology (science)Event Exclusion FOS Protein FOS gene Food Forearm Forelimb Future Gene Activation Goals Grant Hand Hour Human Human Resources Immediate-Early Genes Impairment Individual Injury Intervention Ipsilateral Ischemia Lesion Licensing Limb structure Literature Macaca mulatta Maps Marshal Measures Methods Modeling Monkeys Motor Motor Activity Motor Cortex Movement Nature Neurobiology Neurons Occupational Occupational Therapist Occupational Therapy Operative Surgical Procedures Outcome Patients Pattern Performance Pharmacologic Substance Pilot Projects Plexiglas Plexiglass Population Postoperative Period Primates Process Proto-Oncogene Proteins c-fos Recovery Recovery of Function Rehabilitation therapy Research Research Personnel Rewards Shapes Stroke Study models Surveys Techniques Testing Therapeutic Intervention Time Training Treatment Efficacy United States Upper Extremity Videotape Wrist age group aged aging brain base behavior test experience insight internal control ischemic lesion juvenile animal middle age motor control motor deficit neurobiological mechanism nonhuman primate pressure public health relevance retinal rods senescence stroke recovery tool

项目摘要

DESCRIPTION (provided by applicant): Stroke, primarily a disease-state observed in late middle age and early senescence, results in cortical injury that frequently affects motor activity of the extremities. Given the number of individuals that experience a stroke each year there is a critical need to understand the neurobiological basis of functional recovery in the aging brain. The development of a non-human primate model of cortical ischemia with older animals with small, focal unilateral lesions in the area of the motor cortex that controls the upper extremity provides a unique opportunity to not only develop coordination and strength tools to assess impairment and recovery, but also to establish the extent of cortical reorganization in this age group. In the current proposal we plan to use rhesus monkeys to develop a model of cortical ischemia and reorganization that allows for the quantifiable assessment of motor function recovery in young and middle-aged animals. Three newly developed wrist/digit coordination and strength tasks will be used with monkeys that have small, focal unilateral lesions in the area of the motor cortex that controls the forearm, wrist and digits. Once the monkey reaches asymptotic levels of performance, a unilateral lesion will be made in the area of the motor cortex identified as controlling the digits, hand and forearm. The lesion will produce impairment in the use of the contralateral hand. Monkeys will be retested post-operatively. Following completion of testing a subset of monkeys will receive one final intense training session and then will be perfused. Brains will be processed for cFos activation to quantify the expression of the c-fos protein, a marker of immediate early gene activation and cortical activity. This will allow us to conduct a global survey for differentially activated cortical and subcortical regions in each animal resulting from the final testing session. A second group of animals will undergo a second surgery that will consist of electrophysiological techniques used to identify the areas of reorganization of the cortical representation of the forearm, wrist and digits. A second small, focal lesion will then be made in this area of re-organization in order to establish that this area was in fact facilitating the functional recovery observed during post-operative testing. These animals will be re-tested on all tasks for four weeks to establish the presence and extent of a motor deficit similar in magnitude to the deficit recorded after the first surgery. This proposal will develop a model of stroke that allows for the quantitative assessment of hand/digit motor performance following a localized cortical stroke and can be used in future studies to quantify the efficacy of therapeutic treatments aimed at facilitating recovery of motor function. PUBLIC HEALTH RELEVANCE: Stroke, primarily a disease-state observed in late middle age and early senescence, results in cortical injury that frequently affects motor activity of the extremities. Given the number of individuals that experience a stroke each year there is a critical need to understand the neurobiological basis of functional recovery in the aging brain. This grant proposes the development of a rhesus monkey model of stroke using young and middle-aged animals that involves creating focal unilateral damage in the area of the motor cortex that controls the forearm, hand and digits. It will provide a unique opportunity to assess impairment and spontaneous recovery of hand/digit coordination and strength and for the assessment of the areas of cortical reorganization that may be responsible for recovery. Finally, the establishment of this model and the acquisition of extensive baseline data, will allow for a future RO1 application to investigate various pharmaceutical and occupational therapeutic interventions in a middle-aged and aged non-human primates with motor functions and cortical organization most like those of humans.

描述（由申请人提供）：中风，主要是在中年晚期和衰老早期观察到的疾病状态，导致皮质损伤经常影响肢体的运动活动。鉴于每年经历中风的个体数量，需要了解衰老大脑功能恢复的神经生物学基础。在控制上肢的运动皮质区域内，具有小型局灶性单侧病变的年龄较小的单侧病变的老年动物的非人类灵长类动物模型的发展提供了一个独特的机会，不仅可以开发协调和力量工具来评估损害和恢复，而且还可以在这个年龄组中建立皮质恢复的程度。在当前的提案中，我们计划使用恒河猴开发一种皮质缺血模型和重组模型，该模型允许对年轻和中年动物的运动功能恢复进行可量化的评估。三个新开发的腕部/数字协调和力量任务将与在控制前臂，腕部和数字的运动皮质区域中具有较小的局灶性单侧病变的猴子一起使用。一旦猴子达到渐近的性能水平，将在识别为控制数字，手和前臂的运动皮层区域中产生单侧病变。病变将在使用对侧手的使用时会造成损害。猴子将在术后进行重新测试。在完成测试后，一部分猴子将获得一个最终的激烈训练课程，然后将被灌注。将处理大脑以进行CFOS活化，以量化C-FOS蛋白的表达，C-FOS蛋白是早期基因激活和皮质活性的标志。这将使我们能够在最终测试过程中对每种动物中的差异激活的皮质和皮质下区域进行全球调查。第二组动物将进行第二次手术，该手术将由用于识别前臂，手腕和数字的皮质表示重组区域的电生理技术组成。然后将在重组的该区域中进行第二个小局灶性病变，以确定该领域实际上正在促进术后测试期间观察到的功能恢复。这些动物将在所有任务上重新测试四个星期，以确定与第一次手术后记录的赤字相似的运动不足的存在和程度。该提案将开发一种中风模型，该模型允许对局部皮质中风后的手/数字运动性能进行定量评估，并可以在将来的研究中使用，以量化旨在促进运动功能恢复的治疗方法的功效。公共卫生相关性：中风，主要是在中年晚期和早期衰老的疾病状态，导致皮质损伤经常影响四肢运动的运动活动。鉴于每年经历中风的个体数量，需要了解衰老大脑功能恢复的神经生物学基础。该赠款提出了使用年轻和中年动物的恒河猴中风模型的发展，涉及在控制前臂，手和数字的运动皮层区域造成局灶性单方面损害。它将提供一个独特的机会，以评估手/数字协调和力量的减值和自发恢复，并评估可能导致恢复的皮质重组领域。最后，建立该模型并获取广泛的基线数据，将允许将来的RO1应用调查具有运动功能的中年和老年非人类灵长类动物中的各种药物和职业治疗干预措施，具有运动功能和皮质组织，最像人类。