Tangle Formation in P301L Transgenic Mice

P301L 转基因小鼠中缠结的形成

• 批准号: 6908254
• 负责人: MICHAEL L. HUTTON
• 金额: $ 23.55万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6908254
• 关键词: Alzheimer' s disease; Parkinson' s disease; biological models; biomarker; complementary DNA; functional /structural genomics; gene expression; genetically modified animals; immunocytochemistry; laboratory mouse; lipids; microarray technology; molecular pathology; neural degeneration; neurofibrillary tangles; neuropathology; oxidative stress; pathologic process; phosphorylation; polymerase chain reaction; protein kinase; tau proteins

DESCRIPTION (provided by applicant): Tau pathology is a key feature in numerous neurodegenerative disease including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal dementia and parkinsonism linked to chromosome 17. The events preceding the development of neurofibrillary and other types of tau pathology including associated neurodegeneration are largely unknown. Because tissues are generally unavailable from early stage patients with tauopathies, we intend to utilize a novel mouse model that we have generated to study the progression of neurofibrillary pathology. These transgenic mice express human tau containing an FTDP-17 mutation, P301L, and develop tau neurofibrillary tangles, neuronal loss, amyotrophy, and behavioral and motor deficits. The neurofibrillary tangles in these mice recapitulate essentially all of the features of these lesions in Human tauopathies, including Alzheimer's disease, and critically are also associated with neuronal loss. In addition, the distribution of the pathology and the psychomotor deficits in the tau mice resemble some aspects of progressive supranuclear palsy, amyotrophic lateral sclerosisparkinsonism-dementia (ALS-PD) and variants of FTDP-17. In this project we will perform a series of studies to determine the molecular mechanisms that underlie pathogenesis in the tau (P301L) transgenic mice. cDNA generated from midbrain, pons and spinal cord regions from the P301 L tau mice will be subjected to microarray analysis to identify and profile genes that have altered expression levels during the onset and progression of tangle pathology. To study the effect of tau phosphorylation on tangle formation, which has been suggested as a major initiating event in the pathogenesis of tauopathies, P301L animals will be crossed with mice over expressing either GSK3beta or p25, the constitutive activator of cdk5. Both cdk5 and GSK3beta have been proposed as major tau kinases in both normal brain and in the pathogenesis of disease. Finally, to determine if oxidative stress is associated with the pathology seen in the P301L mice, we will look at markers for oxidative damage of DNA, lipid, and protein. The information from this study will provide a greater understanding of the development of neurofibrillary pathology and associated neurodegeneration in tauopathies as well as the factors that can modify the onset and progression of the pathology.

描述（由申请人提供）：tau病理学是众多关键特征 神经退行性疾病，包括阿尔茨海默氏病，进行性疾病 上核麻痹，皮质生肉变性和额颞痴呆，以及 帕金森氏症与17号染色​​体有关。 神经原纤维和其他类型的tau病理学，包括相关的 神经变性基本上未知。因为组织通常是 早期患者的患者无法使用，我们打算利用 我们已经生成的新型小鼠模型研究了 神经原纤维病理学。这些转基因小鼠表达含有人tau FTDP-17突变，P301L，并发展为Tau神经纤维缠结，神经元 损失，肌肌瘤以及行为和运动缺陷。神经原纤维 这些鼠标中的缠结概括了这些小鼠的所有特征 包括阿尔茨海默氏病在内的人类tauopathies的病变，批判性的病变是 也与神经元丧失有关。另外，分布 病理学和tau小鼠的精神运动缺陷类似 进行性上核麻痹，肌萎缩性侧面 硬化症 - parkinsonism dentia（ALS-PD）和FTDP-17的变体。在这个 项目我们将进行一系列研究以确定分子 tau（P301L）转基因小鼠的发病机理的机制。 cDNA 由中脑，POS和脊髓区域产生的P301 L Tau小鼠 将经过微阵列分析，以识别和概述基因 在缠结的发作和进展过程中，表达水平改变了 病理。为了研究tau磷酸化对缠结形成的影响， 这被认为是在 功，P301L动物将与小鼠交叉，以表达两者 GSK3BETA或P25，CDK5的组成型激活剂。 CDK5和GSK3BETA均 在正常大脑和 疾病的发病机理。最后，确定氧化应激是否为 与P301L小鼠中看到的病理相关，我们将研究标记 用于DNA，脂质和蛋白质的氧化损伤。来自此的信息 研究将对发展的发展有更多的了解 aupathies中的神经原纤维病理和相关的神经变性为 以及可以改变病理的开始和进展的因素。