Development and characterization of a novel Clusterin mouse model

新型 Clusterin 小鼠模型的开发和表征

• 批准号: 9065478
• 负责人: John David Fryer
• 金额: $ 7.83万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9065478
• 关键词: Adult; Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Antithymoglobulin; Apolipoprotein E; Apolipoproteins; Behavior; Behavioral; Binding; Biochemical; Biological Assay; Biology; Brain; Cerebral Amyloid Angiopathy; Cerebrum; Code; Data; Dementia; Deposition; Development; Diffuse; Exons; Generations; Genes; Health; Hematoxylin and Eosin Staining Method; Hemorrhage; Hippocampus (Brain); Human; Immune; In Vitro; Individual; Initiator Codon; Interleukin-1 beta; Interleukin-6; Knock-in; Knock-in Mouse; LDL-Receptor Related Protein 2; Lead; Lipopolysaccharides; Lipoproteins; Mediating; Methods; Microglia; Morphology; Mus; Neurofibrillary Tangles; Neurons; Nuclear; Pathology; Peptide Signal Sequences; Peptides; Proteins; RNA Splicing; Radiation induced damage; Role; Senile Plaques; Signal Transduction; Site; Staining method; Stains; Stroke; TNF gene; Testing; Toxic effect; Transcript; Variant; Vascular Diseases; abeta deposition; astrogliosis; behavior test; brain parenchyma; cohort; extracellular; genetic risk factor; genome wide association study; immune activation; in vivo; inflammatory marker; injured; malignant breast neoplasm; mouse model; neurotoxicity; novel; novel therapeutics; promoter; receptor; sulfated glycoprotein 2; tau Proteins; white matter change

 DESCRIPTION (provided by applicant): Alzheimer disease (AD) is the most common cause of dementia and is characterized by extracellular plaques formed by the deposition of amyloid-ß (Aß) peptide and intracellular tangles comprised of hyperphosphorylated forms of the tau protein. Another common pathology in AD is cerebral amyloid angiopathy (CAA), caused by Aß deposition in the walls of cerebral vessels leading to vascular dysfunction and hemorrhage. The strongest genetic risk factor for both AD and CAA is e4 allele of the apolipoprotein E (APOE) gene, but multiple recent genome-wide association studies have proven that a similar apolipoprotein, Clusterin (CLU), also confers risk for AD. While much is known about apoE biology, much less is known about CLU biology but several lines of evidence indicate that key differences may exist between human and mouse CLU protein. Studies from many years ago demonstrated that CLU is a critical factor in mediating the neurotoxicity associated with amyloid plaques in vivo through some unknown signaling mechanism. The objective of this application is to generate a novel humanized CLU mouse in which the entire human CLU locus replaces the endogenous mouse Clu locus. These mice will be characterized by behavioral, biochemical and histological methods at baseline as well as after immune challenge with lipopolysaccharide. This new mouse model will be useful not only for AD but also for stroke and breast cancer given the emerging role of CLU in those respective fields.

 描述（由申请人提供）：阿尔茨海默病（AD）是痴呆症最常见的病因，其特征是淀粉样蛋白-β（A β）肽沉积形成的细胞外斑块和由tau蛋白过度磷酸化形式组成的细胞内缠结。AD中的另一种常见病理是脑淀粉样血管病（CAA），其由脑血管壁中的淀粉样蛋白沉积引起，导致血管功能障碍和出血。AD和CAA最强的遗传风险因素是载脂蛋白E（APOE）基因的e4等位基因，但最近的多项全基因组关联研究已经证明，类似的载脂蛋白，脂蛋白胆固醇（CLU），也赋予AD的风险。虽然对apoE生物学的了解很多，但对CLU生物学的了解少得多，但几条证据表明人类和小鼠CLU蛋白之间可能存在关键差异。多年来的研究表明，CLU是通过一些未知的信号传导机制介导体内淀粉样斑块相关神经毒性的关键因子。本申请的目的是产生新的人源化CLU小鼠，其中整个人CLU基因座替代内源性小鼠Clu基因座。这些小鼠将在基线时以及用脂多糖免疫激发后通过行为、生化和组织学方法进行表征。这种新的小鼠模型不仅对AD有用，而且对中风和乳腺癌也有用，因为CLU在这些领域中的作用正在显现。