Inflammation and the Ubiquitin/Proteasome Pathway in Neurodegeneration.

神经变性中的炎症和泛素/蛋白酶体途径。

基本信息

批准号：
7731801
负责人：
MARIA Emilia FIGUEIREDO-PEREIRA
金额：
$ 43.95万
依托单位：
HUNTER COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-15 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7731801
关键词：
26S proteasome 9-deoxy-delta-9-prostaglandin D2 Address Adult Alkylation Animal Model Anti-Inflammatory Agents Anti-inflammatory Astrocytes Binding Brain Cell Culture Techniques Cell Death Cell model Cells Chronic Corpus striatum structure Cysteine Data Disease model Dopaminergic Cell Dose Event Family Glutathione Goals Human Hydrolase Inflammation Inflammation Mediators Inflammatory Lead Lewy Bodies Link Living Wills Mediating Microglia Midbrain structure Mitochondria Modeling Mus Nerve Degeneration Neuroblastoma Neurodegenerative Disorders Neuroglia Neuronal Injury Neurons Oxidation-Reduction Oxidative Stress Parkinson Disease Pathogenesis Pathologic Pathologic Processes Pathology Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Play Post-Translational Protein Processing Production Prostaglandin D2 Prostaglandin-Endoperoxide Synthase Prostaglandins Proteins Publishing Rattus Reaction Role Series Small Interfering RNA Substantia nigra structure Sulfhydryl Compounds Therapeutic Ubiquitin Work cyclopentenone dopaminergic neuron in vivo male molecular pathology mouse model multicatalytic endopeptidase complex neuroinflammation neurotoxic nigrostriatal pathway novel prevent progressive neurodegeneration protein aggregate protein aggregation protein degradation public health relevance response synuclein

项目摘要

DESCRIPTION (provided by applicant): Chronic inflammation is a critical factor in the pathogenesis of Parkinson's disease (PD). Neuronal and glial prostaglandins mediate proinflammatory responses, but there is a profound gap in our understanding of how cyclooxygenases and their prostaglandin products redirect cellular events to promote neurodegeneration. We propose studies to address this crucial omission. We will focus on inflammatory cyclopentenone prostaglandins, such as prostaglandin J2 (PGJ2), because they are potently neurotoxic. Our working hypothesis is that the "inflammatory mediator" PGJ2 plays a critical role in initiating progressive PD neurodegeneration. PGJ2 is derived spontaneously from PGD2, the major prostaglandin in the mammalian CNS. PGJ2 is a highly reactive and neurotoxic prostaglandin. PGJ2 is unique among the prostaglandin family because it covalently reacts with free sulfhydryls of glutathione and cysteine residues in cellular proteins, thus it is present in vivo primarily as Michael conjugates. Electrophile binding (S-alkylation) by endogenous compounds such as PGJ2 is regarded as playing an important role in determining whether neurons will live or die. We propose that this covalent protein modification by PGJ2 in the brain represents a novel pathogenic post-translational modification and plays a critical role in PD neurodegeneration. SPECIFIC AIM #1: Examine how PGJ2 causes ubiquitin/1-synuclein aggregation & its role in cell death Lewy bodies (LB) are a pathologic hallmark of PD. The major LB components are ubiquitinated proteins and 1-synuclein. The mechanisms leading to protein aggregation and its role in PD neurodegeneration remain unclear. We will investigate mechanisms induced by PGJ2 that lead to aggregation of ubiquitinated proteins/1- synuclein and cell death in (a) human dopaminergic-like neuroblastoma SK-N-SH cells, (b) rat ventral midbrain (dopaminergic) and (c) cortical neuronal cultures. Our experimental approach includes pharmacological manipulations and diminishing 1-synuclein expression by siRNA. These studies will characterize mechanisms by which PGJ2 causes PD neurodegeneration. SPECIFIC AIM #2: Characterize and optimize our novel PGJ2-induced model of Parkinson's disease The neuroinflammation hypothesis for PD is well accepted. However, there is still a profound gap in our understanding of how products of inflammation promote PD neurodegeneration. We established the first strong model in which an endogenous highly reactive product of inflammation, PGJ2, convincingly induces PD pathology. Our novel PGJ2-induced PD model strongly supports the hypothesis that localized and chronic production (by neurons and/or glia) of highly reactive and neurotoxic cyclopentenone PGJ2 establishes a link between neuroinflammation and PD neurodegeneration. By elucidating the neurotoxic events mediated by prostaglandins, we will be opening up new and important possible targets for pharmaceutical treatment of PD. PUBLIC HEALTH RELEVANCE: Chronic inflammation is a critical factor in the pathogenesis of Parkinson's disease (PD). The studies proposed in this application will elucidate mechanisms, such as alterations in intracellular protein turnover, by which products of inflammation contribute to neuronal injury. These studies are highly significant because a better understanding of the mechanisms by which products of inflammation mediate neuronal injury will lead to more effective anti-inflammatory therapeutic strategies for neurodegenerative disorders, such as PD that are associated with chronic inflammation.

描述（由申请人提供）：慢性炎症是帕金森病（PD）发病机制的关键因素。神经元和神经胶质前列腺素介导促炎症反应，但我们对环氧合酶及其前列腺素产物如何重定向细胞事件以促进神经变性的理解存在巨大差距。我们提出研究来解决这一重要的遗漏。我们将重点关注炎症性环戊烯酮前列腺素，例如前列腺素 J2 (PGJ2)，因为它们具有潜在的神经毒性。我们的工作假设是“炎症介质”PGJ2 在引发进行性 PD 神经变性中发挥着关键作用。 PGJ2 自发衍生自 PGD2，PGD2 是哺乳动物 CNS 中的主要前列腺素。 PGJ2 是一种高反应性和神经毒性的前列腺素。 PGJ2 在前列腺素家族中是独特的，因为它与细胞蛋白质中谷胱甘肽和半胱氨酸残基的游离巯基发生共价反应，因此它在体内主要以迈克尔缀合物的形式存在。 PGJ2 等内源性化合物的亲电结合（S-烷基化）被认为在决定神经元的生存或死亡方面发挥着重要作用。我们认为，大脑中 PGJ2 的这种共价蛋白修饰代表了一种新型致病性翻译后修饰，在 PD 神经变性中发挥着关键作用。具体目标#1：检查 PGJ2 如何引起泛素/1-突触核蛋白聚集及其在细胞死亡中的作用路易体 (LB) 是 PD 的病理标志。 LB 的主要成分是泛素化蛋白和 1-突触核蛋白。导致蛋白质聚集的机制及其在帕金森病神经变性中的作用仍不清楚。我们将研究 PGJ2 诱导的机制，这些机制导致 (a) 人多巴胺能样神经母细胞瘤 SK-N-SH 细胞、(b) 大鼠腹侧中脑（多巴胺能）和 (c) 中泛素化蛋白/1-突触核蛋白聚集和细胞死亡皮质神经元培养。我们的实验方法包括药理学操作和通过 siRNA 减少 1-突触核蛋白表达。这些研究将描述 PGJ2 引起 PD 神经变性的机制。具体目标#2：表征和优化我们新型 PGJ2 诱导的帕金森病模型 PD 的神经炎症假说已被广泛接受。然而，我们对炎症产物如何促进帕金森病神经变性的理解仍然存在很大差距。我们建立了第一个强模型，其中内源性高反应性炎症产物 PGJ2 令人信服地诱导 PD 病理。我们的新型 PGJ2 诱导的 PD 模型强烈支持这样的假设：高反应性和神经毒性环戊烯酮 PGJ2 的局部和慢性产生（由神经元和/或神经胶质细胞）在神经炎症和 PD 神经变性之间建立了联系。通过阐明前列腺素介导的神经毒性事件，我们将为帕金森病的药物治疗开辟新的、重要的可能靶点。公共卫生相关性：慢性炎症是帕金森病 (PD) 发病机制的关键因素。本申请中提出的研究将阐明炎症产物导致神经元损伤的机制，例如细胞内蛋白质周转的改变。这些研究非常重要，因为更好地了解炎症产物介导神经元损伤的机制将有助于针对神经退行性疾病（例如与慢性炎症相关的帕金森病）制定更有效的抗炎治疗策略。