Functions of human and mouse Trem2 in vivo

人和小鼠 Trem2 的体内功能

• 批准号: 9248837
• 负责人: John David Fryer
• 金额: $ 19.56万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248837
• 关键词: Affect; Affinity; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amino Acids; Amyotrophic Lateral Sclerosis; Apolipoprotein E; Area; Behavior; Binding; Biological Assay; Cells; Clinic; Code; Data; Dementia; Disease; Disease Progression; Frontotemporal Dementia; Generations; Genes; Genetic Recombination; Genotype; Germ Lines; Gliosis; Histologic; Human; Immune; Immune system; Immunization; In Vitro; Inflammation; Inflammatory; Innate Immune System; Knock-in; Knock-in Mouse; Link; Lipids; Lipopolysaccharides; Lipoprotein Binding; Lipoprotein Receptor; Lipoproteins; Metabolism; Microglia; Modeling; Mus; Mutation; Myeloid Cells; Nature; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Odds Ratio; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Play; Prosencephalon; Proteins; Receptor Signaling; Risk; Risk Factors; Role; Shapes; Signal Transduction; Symptoms; TREM2 gene; TYROBP gene; Testing; Time; Variant; abeta deposition; brain cell; cholinergic; extracellular; gain of function; genetic risk factor; in vivo; loss of function; mouse genome; mutant; neuron loss; new therapeutic target; novel; peptide B; public health relevance; rare variant; receptor function; tau Proteins

 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-β (Aβ) peptide and intracellular tangles comprised of hyperphosphorylated forms of the tau protein. Gliosis and inflammation are associated with areas of heavy pathology and likely play a key role in shaping disease progression. Microglia, the immune cells of the central nervous system (CNS), are increasingly recognized for their critical roles in the pathogenesis of AD and other neurodegenerative diseases such as frontotemporal dementia (FTD) and Parkinson disease (PD). The strongest genetic risk factor for both AD and CAA is ε4 allele of the apolipoprotein E (APOE) gene, but recently the TREM2 locus was identified as a risk factor for AD with the most significantly associated coding variant as rs75932628 (encoding R47H) with an odds ratio rivaling that of APOE. Because human and mouse Trem2 differ by ~25% at the amino acid level, we aim to create novel knock-in mouse lines that express normal human TREM2 or the TREM2-R47H variant in place of the endogenous mouse Trem2 locus. Characterizing these novel lines along with our existing Trem2-/- mouse line either at baseline or upon immune stimulation will allow us to fundamentally answer whether the TREM2-R47H variant functions as a loss of function or gain of function. Additionally, we have recently found that TREM2 can serve as a receptor for lipoproteins. These mice will be critical in developing new therapeutics that target TREM2 in the context of neurodegeneration and in testing the functional effects of lipoprotein binding to normal vs R47H variant of TREM2.

 描述（由申请人提供）：阿尔茨海默病（AD）是痴呆症的最常见病因，其特征在于淀粉样蛋白-β（Aβ）肽沉积形成的细胞外斑块和由过度磷酸化形式的tau蛋白组成的细胞内缠结。神经胶质增生和炎症与严重病理区域相关，并可能在形成疾病进展中发挥关键作用。小胶质细胞是中枢神经系统（CNS）的免疫细胞，其在AD和其他神经退行性疾病如额颞叶痴呆（FTD）和帕金森病（PD）的发病机制中的关键作用日益被认识。AD和CAA的最强遗传风险因素是载脂蛋白E（APOE）基因的ε4等位基因，但最近TREM 2基因座被确定为AD的风险因素，最显著相关的编码变体为rs75932628（编码R47 H），其比值比与APOE相当。因为人和小鼠Trem 2在氨基酸水平上相差约25%，所以我们的目标是创建表达正常人TREM 2或TREM 2-R47 H变体代替内源小鼠Trem 2基因座的新型敲入小鼠系。在基线或在免疫刺激后表征这些新品系沿着我们现有的Trem 2-/-小鼠品系将允许我们从根本上回答TREM 2-R47 H变体是作为功能丧失还是功能获得发挥作用。此外，我们最近发现TREM 2可以作为脂蛋白的受体。这些小鼠将在神经变性背景下开发靶向TREM 2的新疗法以及测试脂蛋白与TREM 2的正常与R47 H变体结合的功能效应方面至关重要。