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

衰老与帕金森病：治疗学和神经系统共病模型。这是辛辛那提大学尤德尔帕金森病卓越中心的A2申请，由Timothy J. Collier博士指导。帕金森病（PD）的两个研究较少的方面是与疾病和治疗不良后果发展相关的神经机制（如抑郁症和治疗性运动障碍）和与转化治疗相关的机制（如丘脑下核DBS和祖细胞ceU移植）。此外，人们早就认识到年龄增长是帕金森病的主要危险因素，但很少将衰老纳入实验研究。因此，本提案将这些主题分组在“适应和不适应可塑性”的标题下，并在实际年龄增长的背景下研究它们的表达。该方案由四个项目和两个相互连接并服务于项目的核心组成。项目1研究了在移植多巴胺（DA）神经元提供的次优恢复和治疗性运动障碍的发展中，脊柱形态的不适应变化的作用。项目2将确定丘脑下核高频电刺激对DA系统的神经保护程度和机制。特别是，刺激对神经营养机制的影响将被检查。项目3验证了移植未分化神经祖细胞ceu后受损黑质纹状体系统结构和功能的保存不是移植细胞替代DA神经元的产物，而是由移植物诱导的成熟宿主DA神经元的保护和/或再生介导的。项目4的目标是深入了解PD、压力、焦虑和抑郁的共同影响。它将验证共病性抑郁症通过有害的糖皮质激素机制加剧PD相关的行为缺陷、神经化学异常和神经变性的假设。AH项目将利用成熟的大鼠模型，并在实际年龄增长的背景下检查机制和结果的异同。在某种程度上，可塑性是PD的特征，它提供了利用其治疗效果和减少其负面影响的途径。

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.