Pathophysiology and therapeutic testing in a new monkey model of parkinsonism

帕金森病新猴模型的病理生理学和治疗测试

• 批准号: 7469853
• 负责人: ROBERT STERLING TURNER
• 金额: $ 19.79万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7469853
• 关键词: Address; Advanced Development; Animal Model; Animals; Appearance; Behavioral; Bradykinesia; Brain region; Cells; Chronic; Clinical; Complement; Convection; Corpus striatum structure; Defect; Denervation; Development; Disease; Disease model; Dopamine; Dopamine Antagonists; Dopamine Receptor; Ensure; Family; Financial compensation; Fire - disasters; Functional disorder; Genes; Globus Pallidus; Goals; Grant; Impairment; Individual; Infusion procedures; Link; Location; MPTP Poisoning; Measures; Methods; Modeling; Monkeys; Motor; Movement; Muscle Rigidity; Muscle Tonus; Muscle Tremors; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotoxins; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathology; Patients; Population; Prevalence; Primates; Public Health; Regulation; Relative (related person); Rest; Rodent; Secondary to; Severities; Site; Structure; Study models; Symptoms; Testing; Textbooks; Therapeutic; Time; Translating; Tremor; Variant; design; disability; dopaminergic neuron; gene therapy; kinematics; neurotransmission; nonhuman primate; putamen; research study; reuptake

DESCRIPTION (provided by applicant): Rational refinement and targeting of therapies for Parkinson's disease (PD) will be facilitated by an ability to analyze relationships between the pathologic features of the disease and symptoms. Neurotoxin models, however, are limited in their ability to break down the disease into its component features. This problem is exacerbated by two complications that are coming to greater recognition: 1) loss of dopamine (DA) is by no means restricted to the striatum in idiopathic PD or in neurotoxin models of the disease; and 2) individual DA neurons innervate multiple brain regions. We propose a monkey model for studying the pathologic underpinnings of parkinsonism that overcomes the hurdles presented by these complications. Reversible intracerebral blockade of DA neurotransmission will afford precise control over the location of DA loss/blockade, its spatial extent and severity, and its timecourse. It is precisely these aspects of DA dysfunction that are difficult if not impossible to control using neurotoxins. The proposed experiments will use DA antagonists to address the central, yet persistent, question whether loss of DA from the striatum alone can generate the cardinal signs of PD. Although akinesia, bradykinesia, tremor and rigidity are commonly attributed to striatal loss of DA, idiopathic PD and neurotoxin-induced parkinsonism are marked by DA loss in other structures as well. The first aim will determine if these signs can be reproduced in primates by transient antagonism of DA receptors (both D1 and D2) in the motor striatum. Convection-enhanced delivery will be used to produce a homogeneous blockade of DA receptors within significant portions of the posterior putamen (site of the most severe DA loss in idiopathic PD). Parkinsonian signs will be measured using tasks designed to manipulate relevant behavioral parameters: movement initiation/sequencing (akinesia), movement kinematics (bradykinesia), tremor, and muscle tone (rigidity). The internal globus pallidus is a critical link in the translating the DA dysfunction of PD into parkinsonian signs. The second aim will determine which abnormalities in the firing of globus pallidus neurons can be attributed directly to the loss of striatal DA and thus contribute to the impairments elicited. This aim will also correlate specific abnormalities in pallidal firing with the appearance of specific parkinsonian symptoms. PUBLIC HEALTH RELEVANCE: Despite the growing prevalence of Parkinson's disease in the population, refinement and accurate anatomical targeting of new treatments is impeded by our rudimentary understanding of the relationship between the pathology of the disease (i.e., which cells die) and its symptoms. The animal model and experiments proposed here will provide important new information about the critical pathologic defects that give rise to parkinsonian signs. Target selection for new cell and gene therapies will be guided by this information.

描述（由申请人提供）：帕金森病（PD）治疗的合理优化和靶向将通过分析疾病病理特征与症状之间关系的能力来促进。然而，神经毒素模型在将疾病分解为其组成特征的能力方面是有限的。这一问题因两种越来越被认识到的并发症而加剧：1）多巴胺（DA）的损失绝不限于特发性PD或该疾病的神经毒素模型中的纹状体;以及2）单个DA神经元支配多个脑区域。我们提出了一种猴模型，用于研究帕金森综合征的病理基础，克服了这些并发症所带来的障碍。可逆的DA神经传递的脑内阻滞将提供精确的控制DA损失/阻滞的位置，其空间范围和严重程度，以及其时间进程。正是这些方面的DA功能障碍，是困难的，如果不是不可能控制使用神经毒素。拟议的实验将使用DA拮抗剂来解决中心的，但持久的问题，是否从纹状体单独的DA损失可以产生PD的主要迹象。虽然运动不能、运动迟缓、震颤和强直通常归因于纹状体DA的丢失，但特发性PD和神经毒素诱导的帕金森综合征也以其他结构中的DA丢失为标志。第一个目标将确定这些迹象是否可以通过运动纹状体中DA受体（D1和D2）的短暂拮抗作用在灵长类动物中重现。对流增强递送将用于在后壳核的重要部分（特发性PD中最严重的DA损失部位）内产生DA受体的均匀阻断。将使用设计用于操纵相关行为参数的任务来测量帕金森病体征：运动启动/排序（运动不能）、运动学（运动迟缓）、震颤和肌张力（僵硬）。内部苍白球是将PD的DA功能障碍转化为帕金森病体征的关键环节。第二个目标将确定哪些异常的苍白球神经元的发射可以直接归因于纹状体DA的损失，从而有助于引起的损害。这一目标也将苍白球放电的特殊异常与特定帕金森病症状的出现联系起来。公共卫生相关性：尽管帕金森病在人群中的患病率不断增加，但我们对疾病病理学之间的关系（即，哪些细胞死亡）及其症状。动物模型和实验提出这里将提供重要的新信息的关键病理缺陷，引起帕金森氏症的迹象。新的细胞和基因疗法的目标选择将由这些信息指导。