PARKINSON'S DISEASE RESEARCH CENTER AT COLUMBIA

帕金森氏病（PD）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进展，也不能充分控制大多数致残症状。 PD的大多数临床特征是由于黑质腹侧部（SNPC）中多巴胺（DA）神经元的丢失所致。 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的不可阻挡的进展至关重要。 该PD中心的统一主题与PD中的神经变性有关;我们的目标是在实验室项目1-4中揭示其发病机制，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小鼠和表达突变型Cu/Zn超氧化物歧化酶（Msod 1）的转基因小鼠中Snpc神经元的损失。 我们探索我们的观察，MPTP刺激次氯酸，一个高度反应性的组织损伤物种的生产。 通过一系列的DNA链断裂和多聚（ADP-核糖）聚合酶（PARP）激活MPTP模型。 它还将探索增加的胞质DA池导致Snpc神经元变性，并产生细胞质泛素化包涵体，让人想起路易体，PD的标志。项目2研究如何改变细胞内DA在SN神经元的基因工程小鼠的培养触发分子机制，启动DA神经元的变性。 项目3评估了异常再激活的程序性细胞死亡（PCD）（正常发生在发育过程中）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、其激酶、JNK、死亡效应物半胱天冬酶-3以及tau和神经丝激酶cdk 5在多巴胺能Snpc神经元中PCD范例中的作用。 项目4将利用一种新技术，基因表达系列分析（SAGE），鉴定在6-OHDA诱导的单胺能PC 12细胞变性中起作用的基因，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神经变性，项目5将在早期PD患者队列中将纵向临床评价与正电子发射断层扫描（PET）生成的代谢结果相关联。在未来的临床试验中，开发生物标志物是评估疾病进展的必要条件，以测试潜在的神经保护疗法。 项目6是一项流行病学研究，旨在解释黑人和妇女中PD患病率较低的原因;除其他假设外，它将评估生物学差异可能影响进展率的可能性。

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.