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.

衰老和帕金森氏病：治疗和神经系统合并症的模型。这是由蒂莫西·J·科利尔（Timothy J. Collier）博士执导的辛辛那提大学的Udall Parkinson病卓越中心的A2申请。帕金森氏病（PD）的两个较少研究的方面是与疾病和治疗不良后果的发展有关的神经机制（例如抑郁症和治疗诱导的运动障碍）以及与转化治疗（例如下allamic核DBS和祖先DBS和祖先CEU CEU）相关的机制。此外，长期以来，人们一直认为，前进的年龄是PD的主要危险因素，但衰老很少被纳入实验研究中。因此，本提案将这些主题分组为“适应性和适应性可塑性”的标题，并在促进时间顺序时代的背景下检查了它们的表达。该提案由四个项目和两个核心组成，它们相互连接并为项目提供服务。项目1研究了脊柱形态的不良适应性变化在嫁接多巴胺（DA）神经元提供的次优恢复中的作用以及治疗引起的运动障碍的发展。项目2将确定由丘脑下核的高频电刺激赋予的DA系统的神经保护程度和机制。特别是，可以检查对神经营养机制的刺激作用。项目3检验了以下假设：在植入未分化的神经祖细胞CEUS CEUS植入后受伤的黑质体系的结构和功能并不是接枝细胞替换DA神经元的产物，而是由移植物诱导的保护和/或Mature宿主DA神经元的介导的。项目4的目标是深入了解PD，压力，焦虑和抑郁的共同融合。它将检验以下假设，即合并症抑郁加剧了通过有害的糖皮质激素机制与PD相关的行为缺陷，神经化学异常和神经变性。 AH项目将利用良好的大鼠模型，并在延长时间顺序的年龄的背景下检查机制和结果的差异和相似之处。在一定程度上，可塑性是PD的特征，它提供了利用其治疗效果并减少其负面影响的访问点。