Functions of human and mouse Trem2 in vivo

人和小鼠 Trem2 的体内功能

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

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-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）是痴呆症的最常见原因，其特征是淀粉样蛋白-β（Aβ）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。炎症与严重病理区域相关，并且可能在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，因其在疾病进展中的关键作用而得到越来越多的认可。 AD 和额颞叶痴呆 (FTD) 和帕金森病 (PD) 等其他神经退行性疾病的发病机制 AD 和 CAA 最强的遗传风险因素是载脂蛋白 E (APOE) 基因的 ε4 等位基因，但最近发现了 TREM2 基因座。作为 AD 的危险因素，最相关的编码变体为 rs75932628（编码 R47H），其比值显着与人类和小鼠的 APOE 相媲美。 Trem2 在氨基酸水平上相差约 25%，我们的目标是创建表达正常人 TREM2 或 TREM2-R47H 变体的新型敲入小鼠系，以代替内源性小鼠 Trem2 基因座，并与我们现有的小鼠系一起表征这些新系。 Trem2-/- 小鼠品系无论是在基线还是在免疫刺激后，都将使我们能够从根本上回答 TREM2-R47H 变体的功能是功能丧失还是功能增强。此外，我们最近发现 TREM2。这些小鼠对于开发针对神经退行性变的 TREM2 的新疗法以及测试脂蛋白与正常 TREM2 与 R47H 变体结合的功能效果至关重要。