Dopamine, mutant synuclein, oxidative stress and inflammation

多巴胺、突变突触核蛋白、氧化应激和炎症

• 批准号: 7929547
• 负责人: HOWARD J. FEDEROFF
• 金额: $ 45.21万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929547
• 关键词: Address; Affinity; Age; Age-Months; Alkaline Phosphatase; Amphetamines; Amyloid; Animal Model; Animals; Antibodies; Antioxidants; Astrocytes; Attenuated; Automobile Driving; Autoradiography; Behavioral; Binding; Biochemical; Biological Assay; Bradykinesia; Brain; CCL2 gene; CD36 gene; Caregivers; Cell Death; Cells; Chemistry; Cogwheel Rigidity; Collaborations; Corpus striatum structure; Coupled; Cultured Cells; Cytoplasmic Inclusion; Data; Defect; Degenerative Disorder; Disease; Dissection; Dopamine; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Epidemiology; Event; Exhibits; Failure; Fiber; Freezing; Functional disorder; Gene Expression; Genes; Glial Fibrillary Acidic Protein; Goals; High Pressure Liquid Chromatography; Human; IL8 gene; Immune response; Immunoprecipitation; Immunotherapy; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inherited; Injection of therapeutic agent; Injury; Interleukin-1; Interleukin-6; Interruption; Investigation; Label; Lead; Lewy Bodies; Macrophage Inflammatory Protein-1; Mass Spectrum Analysis; Measurement; Measures; Mediating; Mediator of activation protein; Membrane; Metabolism; Microfluidics; Microglia; Modification; Monocyte Chemoattractant Protein-1; Motion; Motor; Mus; Mutation; Neurites; Neurodegenerative Disorders; Neurons; Nitroblue Tetrazolium; Outcome; Oxidants; Oxidative Stress; Paraquat; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; Phagocytosis; Preparation; Presynaptic Terminals; Process; Production; Proteins; Quinones; RNA; Rattus; Reagent; Reporter; Reporter Genes; Reporting; Response Elements; Rest Tremor; Role; Rotenone; SR-B proteins; Signal Transduction; Site; Slice; Staining method; Stains; Stress; Substantia nigra structure; Symptoms; Synapses; TNF gene; Testing; Therapeutic; Toxic effect; Transgenes; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Two-Dimensional Gel Electrophoresis; Tyrosine 3-Monooxygenase; Up-Regulation; Viral; Western Blotting; Work; alpha synuclein; attenuation; base; biological adaptation to stress; cell type; chemokine; conformer; cytokine; density; dopamine quinone; dopamine transporter; dopaminergic neuron; extracellular; feeding; gene environment interaction; in vivo; inflammatory marker; islet amyloid polypeptide; isopentane; mouse model; mutant; neurochemistry; nigrostriatal pathway; overexpression; oxidant stress; paraform; polyclonal antibody; presynaptic; promoter; receptor; receptor density; research study; response; retrograde transport; scavenger receptor; synuclein; tissue culture; toxicant

Parkinson's disease is a slowly progressive degenerative disorder with classic motor symptoms that include resting tremor, cogwheel rigidity and bradykinesia. The disease produces invariant loss of dopamine neurons in the substantia nigra (SN) with the hallmark pathological features of activated microglia and proteinaceous cytoplasmic inclusions called Lewy bodies in the remaining neurons. Epidemiological data supports that gene-environment interactions are responsible for the largest proportion of sporadic PO cases. One of the key issues in PO is the identification of the initiating triggering mechanism(s) and the locus of its injury. Efforts to elucidate th·ls mechanism have been aided by the linkage between toxicant (e.g., MPTP, paraquat. rotenone) injury, oxidative stress, inherited defects in turnover of the presynaptic and Lewy Body constituent protein a-synuclein (SYN), and involvement of cytosolic dopamine. Using established animal models of wild-type (wtSYN+/+) and mutant SYN (dmSYN+/+) overexpression in OA producing cells we will address the hypothesis that an early effect of SYN overexpression is increased microglial activation and proinflammatory processes leading to presynaptic dysfunction. We further posit that wtSYN and dmSYN activate microglia differentially but both result in an increased quinone oxidant response. Three aims are proposed to test this hypothesis: Ai m 1. Characterization of microglial activation and presynaptic function in mice overexpressing wild-type (wtSYN+/+) or double-mutant SYN (dmSYN+/+); Aim 2. Characterization of the proinflammatory response to wtSYN and dmSYN: Aim 3. Examination of the role of quinone-mediated oxidative stress in microglial activation. We will utilize several unique transgenic mouse models including wtSYN+/+ that overexpress wIld-type SYN, dmSYN+/+ that overexpress mutant SYN, wtSYN+/+::AREhPLAP and dmSYN+/+::AREhPlAP which overexpress SYN in the background of a mouse capable of reporting quinone-mediated stress. These studies will produce clear and interpretable data concerning the role of microglia in the presynaptic injury elicited by SYN. Parkinson 's Disease (PO) is the second most common neurodegenerative disease and impacts both patients and their caregivers. The goal of this project is to evaluate the progressive changes in the brain during PD. We focus our work on both tissue culture and animal models of PO and ask what is the role of pro-inflammatory molecules and microglia in disease initiation and progression . Particularly we will study early changes in PD. The results of these studies may lead to the identIfication of potential therapies for PD.

帕金森氏病是一种缓慢的进行性退化性疾病，经典马达 症状，包括静止震颤，齿轮刚度和胸肌。该疾病会产生 具有标志性病理特征的黑质Nigra（SN）中多巴胺神经元的不变丧失 活化的小胶质细胞和蛋白质细胞质夹杂物，称为Lewy体 神经元。流行病学数据支持基因 - 环境相互作用负责 零星PO病例中最大的比例。 PO的关键问题之一是确定 启动触发机制及其受伤的根源。阐明这种机制的努力 有助于毒物（例如MPTP，paraquat。Rotenone）损伤，氧化应激，氧化应激之间的联系，以帮助 遗传性缺陷在突触前和Lewy身体成分蛋白A-核蛋白（SYN），，， 和胞质多巴胺的参与。使用野生型的既定动物模型（WTSYN+/+）和 OA产生细胞中的突变体Syn（DMSYN+/+）过表达我们将解决以下假设。 SYN过表达的早期作用是小胶质激活和促炎性的增加 导致突触前功能障碍的过程。我们进一步确认WTSYN和DMSYN 以不同的方式激活小胶质细胞，但两者都会导致醌氧化物的反应增加。 提出了三个目的来检验以下假设：AI M 1。小胶质激活的表征和 过表达野生型（WTSYN+/+）或双突出SYN（DMSYN+/+）的小鼠中突触的起突触功能； 目标2。对WTSYN和DMSYN的促炎反应的表征：AIM 3。 喹酮介导的氧化应激在小胶质细胞活化中的作用。我们将利用几种独特的 转基因小鼠模型，包括WTSYN+/+过表达野生型SYN，DMSYN+/+ 过表达突变体SYN，WTSYN+/+:: AREHPLAP和DMSYN+/+:: AREHPLAP过表达 在小鼠的背景下进行的SYN能够报告喹酮介导的应激。这些研究会 产生有关小胶质细胞在突触前损伤中的作用的清晰可解释的数据 由Syn。 帕金森氏病（PO）是第二大最常见的神经退行性疾病，两者都影响 病人及其护理人员。该项目的目的是评估 PD期间的大脑。我们将工作重点放在PO的组织文化和动物模型上，并询问什么是 促炎分子和小胶质细胞在疾病起始和进展中的作用。特别 我们将研究PD的早期变化。这些研究的结果可能导致鉴定 PD的潜在疗法。