PARKINSONS DISEASE RESEARCH CENTER

帕金森病(P-D)是一种常见的神经退行性疾病，以运动迟缓、僵硬和震颤为特征；目前的治疗方法既不能减缓进展，也不能充分控制最致残的症状。帕金森病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。到目前为止，帕金森病的病因和发病机制尚不清楚。这些知识对于学习如何防止帕金森病的不可阻挡的进展至关重要。这个PD中心的统一主题与PD的神经变性有关；我们的目标是在实验室项目1-4中揭开其发病机制，并在临床项目5-6中量化其进展。项目1研究了两种PD的动物模型，即MPTP小鼠和表达突变的铜/锌超氧化物歧化酶(Msod1)的转基因小鼠中SNPC神经元的丢失。我们探索我们的观察结果，MPTP刺激次氯酸的产生，次氯酸是一种高活性的组织损伤物种。在MPTP模型中，通过一系列的DNA链断裂和聚腺苷二磷酸核糖聚合酶(PARP)的激活。它还将探索胞浆DA池的增加导致SNPC神经元的退化，并产生使人想起路易小体的细胞质泛素化包涵体，这是帕金森病的一个特征。项目2研究了从基因工程小鼠的黑质神经元培养中改变细胞内DA如何触发分子机制来启动DA神经元的退化。项目3评估了异常重新激活的程序性细胞死亡(PCD)(在发育过程中正常发生)在帕金森病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、死亡效应因子caspase-3、tau和神经丝蛋白激酶cdk5在多巴胺能SNPC神经元中PCD范例中的作用。项目4将利用一种名为基因表达序列分析(SAGE)的新技术来识别在6-OHDA诱导的单胺能PC12细胞退化中发挥作用的基因，然后将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记物来量化人类DA神经退行性变，项目5将在一组早期帕金森病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。在未来测试潜在神经保护疗法的临床试验中，开发生物标记物对于评估疾病进展是必要的。项目6是一项流行病学研究，旨在解释帕金森病在黑人和妇女中的较低患病率；除其他假设外，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.