Aging and Parkinson's Disease: Models of Therapeutics and Neurologic Comorbidity

衰老和帕金森病：治疗模型和神经系统合并症

• 批准号: 7937865
• 负责人: Timothy J. Collier
• 金额: $ 120.13万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937865
• 关键词: Age; Aging; Anxiety; Behavioral; Biological Preservation; Cells; Characteristics; Comorbidity; Deep Brain Stimulation; Development; Disease; Disease model; Doctor of Philosophy; Dyskinetic syndrome; Elderly; Electric Stimulation; Engraftment; Frequencies; Glucocorticoids; Goals; Mediating; Mental Depression; Modeling; Morphology; Natural regeneration; Nerve Degeneration; Neurologic; Outcome; Parkinson Disease; Rattus; Recovery; Risk Factors; Role; Stress; Structure; Structure of subthalamic nucleus; Testing; Therapeutic; Therapeutic Effect; Transplantation; Undifferentiated; Universities; Vertebral column; adverse outcome; dopamine system; dopaminergic neuron; injured; insight; nerve stem cell; neurochemistry; neuromechanism; neuron development; neuroprotection; nigrostriatal system; progenitor; programs; research study

Aging and Parkinson's disease: Models of therapeutics and neurologic comorbidity. This is an A2 application for a Udall Parkinson's Disease Center of Excellence from the University of Cincinnati directed by Timothy J. Collier, Ph.D. Two less studied aspects of Parkinson's disease (PD) are the neural mechanisms associated with development of adverse consequences of disease and treatment (such as depression and therapy-induced dyskinesias) and mechanisms associated with translational therapeutics (such as subthalamic nucleus DBS and progenitor ceU transplantation). In addition, it long has been appreciated that advancing age is a primary risk factor for PD, yet aging rarely is incorporated into experimental studies. Thus, the present proposal groups these topics under the rubric of "adaptive and maladaptive plasticity"and examines their expression in the context of advancing chronological age. The proposal consists of four projects and two cores that interconnect and serve the projects. Project 1 examines the roles of maladaptive changes in spine morphology in suboptimal recovery provided by grafted dopamine (DA) neurons and the development of therapy-induced dyskinesias. Project 2 will determine the degree and mechanism of neuroprotection for the DA system conferred by high frequency electrical stimulation of the subthalamic nucleus. In particular, stimulation effects on neurotrophic mechanisms wUl be examined. Project 3 tests the hypothesis that preservation of the structure and function of the injured nigrostriatal system following engraftment of undifferentiated neural progenitor ceUs is not a product of replacement of DA neurons by grafted cells, but is mediated by graft-induced protection and/or regeneration of mature host DA neurons. The goal of Project 4 is to gain insight into the co-mingling of PD, stress, anxiety and depression. It will test the hypothesis that comorbid depression exacerbates the behavioral deficits, neurochemical abnormalities, and neurodegeneration associated with PD via deleterious glucocorticoid mechanisms. AH projects will utilize well-established rat models and examine differences and similarities of mechanisms and outcomes in the context of advancing chronological age. To the extent that plasticity is characteristic of PD, it provides points of access to harness its therapeutic effects and curtail its negative effects.

衰老与帕金森病：治疗学和神经学共病的模型。这是辛辛那提大学Udall帕金森疾病卓越中心的A2申请，由Timothy J.Collier，Ph.D.指导。帕金森病(PD)的两个较少研究的方面是与疾病和治疗(如抑郁症和治疗诱导的运动障碍)的不良后果的发展相关的神经机制，以及与翻译治疗相关的机制(如丘脑底核DBS和祖细胞CEU移植)。此外，人们很早就认识到，年龄增长是帕金森病的主要危险因素，然而，衰老很少被纳入实验研究。因此，本提案将这些专题归类为“适应性和非适应性可塑性”，并在推进年龄的背景下审查它们的表达。该提案包括四个项目和两个核心，这些核心相互连接并为这些项目服务。项目1考察了脊柱形态的不适应变化在移植的多巴胺(DA)神经元提供的次优恢复中的作用以及治疗诱导的运动障碍的发展。项目2将确定高频电刺激丘脑底核对DA系统的神经保护程度和机制。特别是，对神经营养机制的刺激效应还有待研究。项目3验证了以下假设：未分化神经前体细胞移植后黑质纹状体系统结构和功能的保留不是移植细胞替代DA神经元的产物，而是由移植诱导的成熟宿主DA神经元的保护和/或再生所介导的。项目4的目标是深入了解帕金森病、压力、焦虑和抑郁的共同作用。它将检验一种假设，即共病抑郁通过有害的糖皮质激素机制加剧与帕金森病相关的行为缺陷、神经化学异常和神经退行性变。AH项目将利用已建立的大鼠模型，并在推进实际年龄的背景下检查机制和结果的异同。在一定程度上，可塑性是帕金森病的特征，它提供了利用其治疗效果和减少其负面影响的切入点。