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: 7462858
• 负责人: HOWARD J. FEDEROFF
• 金额: $ 44.02万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7462858
• 关键词: Address; Affect; Affinity; Age; Age-Months; Alkaline Phosphatase; American; Amphetamines; Amyloid; Animal Model; Antibodies; Antioxidants; Attenuated; 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; Dopamine; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Epidemiology; Exhibits; Failure; Fiber; Freezing; Functional disorder; Genes; Goals; High Pressure Liquid Chromatography; Human; Immune response; Immunoprecipitation; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inherited; Injection of therapeutic agent; Injury; Interleukin-1; Interleukin-6; Label; Lead; Lewy Bodies; Mass Spectrum Analysis; Measurement; Mediating; Mediator of activation protein; Membrane; Metabolism; Microfluidics; Microglia; Modification; Motion; Motor; Mus; Mutation; Neurites; Neurodegenerative Disorders; Neurons; Nitroblue Tetrazolium; Outcome; Oxidants; Oxidative Stress; Paraquat; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; 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; Small Inducible Cytokine A3; Staining method; Stains; Stress; Substantia nigra structure; Symptoms; Synapses; Testing; Therapeutic; Transgenes; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Tyrosine 3-Monooxygenase; Western Blotting; Work; alpha synuclein; conformer; density; dopamine quinone; dopamine transporter; dopaminergic neuron; extracellular; feeding; gel electrophoresis; gene environment interaction; inflammatory marker; islet amyloid polypeptide; isopentane; mouse model; mutant; neurochemistry; novel therapeutics; overexpression; paraform; peroxiredoxin; polyclonal antibody; presynaptic; receptor; receptor density; research study; response; retrograde transport; scavenger receptor; synuclein; therapeutic development; 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.

帕金森病是一种缓慢进展的退行性疾病，具有典型的运动障碍 该疾病产生的症状包括静止性震颤、齿轮性僵硬和运动迟缓。 黑质（SN）中多巴胺神经元的恒定丢失具有标志性病理特征 激活的小胶质细胞和称为路易体的蛋白质细胞质内含物在剩余的 流行病学数据支持基因与环境的相互作用是造成这种现象的原因。 零星 PO 案件所占比例最大。 PO 的关键问题之一是识别。 阐明该机制的启动触发机制及其损伤部位已做出了努力。 有毒物质（例如 MPTP、百草枯、鱼藤酮）损伤、氧化应激、 突触前和路易体组成蛋白 a-突触核蛋白 (SYN) 更新的遗传缺陷， 和胞质多巴胺的参与使用已建立的野生型动物模型（wtSYN+/+）和 突变 SYN (dmSYN+/+) 在产生 OA 的细胞中过度表达，我们将提出以下假设： SYN 过表达的早期效应是增加小胶质细胞激活和促炎症 我们进一步定位 wtSYN 和 dmSYN。 不同程度地激活小胶质细胞，但都会导致醌氧化反应增加。 提出了三个目标来检验这一假设： Ai m 1. 小胶质细胞激活的表征和 过度表达野生型 (wtSYN+/+) 或双突变 SYN (dmSYN+/+) 的小鼠的突触前功能； 目标 2. 对 wtSYN 和 dmSYN 的促炎反应的表征：目标 3. 检查 我们将利用几种独特的方法来研究醌介导的氧化应激在小胶质细胞激活中的作用。 转基因小鼠模型，包括过度表达野生型 SYN 的 wtSYN+/+，以及过度表达野生型 SYN 的 dmSYN+/+ 过表达突变体 SYN、wtSYN+/+::AREhPLAP 和 dmSYN+/+::AREhPlAP 过表达 这些研究将在能够报告醌介导的应激的小鼠的背景下进行SYN。 产生关于小胶质细胞在引起的突触前损伤中的作用的清晰且可解释的数据 通过 SYN。 帕金森病 (PO) 是第二常见的神经退行性疾病，影响着两者 该项目的目标是评估患者及其护理人员的渐进变化。 我们的工作重点是 PO 的组织培养和动物模型，并询问什么是 PO。 促炎分子和小胶质细胞在疾病发生和进展中的作用。 我们将研究PD的早期变化，这些研究的结果可能有助于识别PD。 PD 的潜在疗法。