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

衰老和帕金森病：治疗学和神经学共病模型。这是辛辛那提大学Udall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）的两个较少研究的方面是与疾病和治疗的不良后果的发展相关的神经机制（例如抑郁和治疗诱导的运动障碍）和与转化治疗相关的机制（例如丘脑底核DBS和祖细胞移植）。此外，人们早就认识到，年龄增长是PD的主要风险因素，但衰老很少被纳入实验研究。因此，本建议组这些主题下的标题“适应性和适应不良的可塑性“，并检查其表达的背景下，推进实足年龄。该提案由四个项目和两个核心组成，这两个核心相互连接并为项目提供服务。项目1研究了脊柱形态学的适应不良变化在移植多巴胺（DA）神经元提供的次优恢复和治疗诱导的运动障碍的发展中的作用。项目2将确定由丘脑底核的高频电刺激所赋予的DA系统的神经保护的程度和机制。特别地，将检查对神经营养机制的刺激作用。项目3测试的假设，未分化的神经祖细胞植入后的损伤的黑质纹状体系统的结构和功能的保存是不是由移植细胞的DA神经元的替代产品，但介导的移植诱导的保护和/或再生的成熟宿主DA神经元。项目4的目标是深入了解PD，压力，焦虑和抑郁的混合。它将检验共病抑郁症通过有害的糖皮质激素机制加剧与PD相关的行为缺陷、神经化学异常和神经退行性变的假设。AH项目将利用成熟的大鼠模型，并在年龄增长的背景下研究机制和结果的差异和相似性。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.