Development and characterization of a novel Clusterin mouse model

新型 Clusterin 小鼠模型的开发和表征

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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 (Aß) 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 的常见病理是脑淀粉样血管病 (CAA)，由 Aß 沉积在脑血管壁引起，导致血管功能障碍和出血，这是 AD 的最强遗传危险因素。 AD 和 CAA 都是载脂蛋白 E (APOE) 基因的 e4 等位基因，但最近多项全基因组关联研究证明，类似的载脂蛋白 Clusterin (CLU) 也会带来 AD 风险。人们对 CLU 生物学知之甚少，但多项证据表明，人类和小鼠 CLU 蛋白之间可能存在关键差异。多年前的研究表明，CLU 是介导与 CLU 相关的神经毒性的关键因素。本申请的目的是产生一种新型人源化 CLU 小鼠，其中整个人类 CLU 基因座取代了内源性小鼠 CLU 基因座，这些小鼠将通过行为、生化和组织学方法进行表征。鉴于 CLU 在这些领域中的新兴作用，这种新的小鼠模型不仅可用于治疗 AD，还可用于治疗中风和乳腺癌。