PARKINSON'S DISEASE RESEARCH CENTER AT COLUMBIA

帕金森病（P-D）是一种常见的神经退行性疾病，其特征是运动迟缓、僵硬和震颤；目前的治疗既不能减缓病情进展，也不能充分控制最严重的致残症状。PD的大部分临床特征是由于黑质致密部（Snpc）多巴胺（DA）神经元的丢失。迄今为止，PD的病因和发病机制尚不清楚。这些知识对于学习如何预防PD的不可阻挡的进展是至关重要的。这个PD中心的统一主题涉及PD的神经变性；我们的目标是在实验室项目1-4中阐明其发病机制，并在临床项目5和6中量化其进展。项目1研究了两种PD动物模型，即MPTP小鼠Snpc神经元缺失和表达突变体Cu/Zn超氧化物歧化酶（Msod1）的转基因小鼠Snpc神经元缺失。我们探索我们的观察，MPTP刺激生产次氯酸，一个高度反应性的组织损伤物种。在MPTP模型中通过一系列DNA链断裂和聚（adp -核糖）聚合酶（PARP）激活。它还将探讨胞质内DA池的增加导致Snpc神经元变性，并产生细胞质泛素化包涵体，使人想起路易体，这是PD的一个标志。项目2研究基因工程小鼠SN神经元细胞内DA的改变如何触发DA神经元退化的分子机制。项目3评估了异常再激活的程序性细胞死亡（PCD）（在发育过程中正常发生）在PD发病机制中发挥作用的假设。项目3研究了信号分子c-jun、它的激酶、JNK、死亡效应caspase-3、tau和神经丝激酶cdk5在多巴胺能Snpc神经元PCD范式中的作用。项目4将利用一种新技术——基因表达序列分析（SAGE），鉴定在6-羟色胺诱导的单胺能PC12细胞变性中发挥作用的基因，然后确定这些基因在动物模型和POD脑中的表达。为了开发一种生物标志物来量化人类DA神经退行性变，项目5将在一组早期PD患者中，将纵向临床评估和正电子发射断层扫描（PET）产生的代谢结果联系起来。开发一种生物标志物对于评估未来临床试验中潜在的神经保护疗法的疾病进展是必要的。项目6是一项流行病学研究，旨在解释黑人和女性PD患病率较低的原因；在其他假设中，它将评估生物差异可能影响进展速度的可能性。

Parkinson's disease (P-D) is a common neurodegenerative disorder characterized by bradykinesia, rigidity and tremor; current treatments neither slow progression nor adequately control the most disabling symptoms. Most of PD's clinical features result from the loss of dopamine (DA) neurons in the substantia nigra pars compacta (Snpc). Thus far, the cause and pathogenesis of PD are unknown. This knowledge is critical to learn how to prevent PD's inexorable progression. The unifying theme of this PD Center relates to neurodegeneration in PD; our goal is to unravel its pathogenesis in lab projects 1-4 and quantify its progression in clinical projects 5&6. Project 1 investigates two animal models of PD, i.e., loss of Snpc neurons in the MPTP mouse and in the transgenic mouse expressing mutant Cu/Zn superoxide dismutase (Msod1). We explore our observation that MPTP stimulates the production of hypochlorous acid, a highly reactive tissue damaging species. Through a series of DNA strand breakage and poly (ADP-ribose) polymerase (PARP) activation in the MPTP model. It will also explore the increased cytosolic DA pool leads to degeneration of Snpc neurons and produces cytoplasmic ubiquitinated inclusions reminiscent of Lewy bodies, a hallmark of PD. Project 2 investigates how altering intracellular DA in cultures of SN neurons from genetically engineered mice triggers molecular mechanisms to initiate degeneration of DA neurons. Project 3 evaluates the hypothesis that abnormally re-activated programmed cell death (PCD) (which occurs normally during development) plays a role in pathogenesis of PD. Project 3 examines the role of the signaling molecule c-jun, its kinase, JNK, the death effector caspase-3, and a tau and neurofilament kinase cdk5 in paradigms of PCD in dopaminergic Snpc neurons. Project 4 will identify genes that play roles in the 6-OHDA-induced degeneration of monoaminergic PC12 cells utilizing a new technique, Serial Analysis of Gene Expression (SAGE) and then will determine the expression of such genes in animal models and in POD brains. TO develop a biologic marker to quantify DA neurodegeneration in humans, Project 5 will correlate longitudinal clinical evaluations and positron emission tomography (PET)-generated metabolic findings in a cohort of early PD patients. Development of a biomarker is necessary to assess disease progression in future clinical trials testing potential neuroprotective therapies. Project 6 is an epidemiological study designed to explain the lower prevalence rates of PD in Blacks and women; it will evaluate, among other hypotheses, the possibility that biological differences may affect rates of progression.