Modeling the Genetic Interaction Between Klotho and APOE Alleles in Alzheimer's Disease

模拟阿尔茨海默病中 Klotho 和 APOE 等位基因之间的遗传相互作用

• 批准号: 10524407
• 负责人: Gregory W Carter
• 金额: $ 228.18万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10524407
• 关键词: Affect; Age of Onset; Age-Months; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Amyloid deposition; Attenuated; Behavior; Biological; Blood; Brain; Brain region; Cerebral hemisphere; Cerebrospinal Fluid; Cessation of life; Characteristics; Code; Cognitive; Deposition; Development; Disease; Exhibits; Fibroblast Growth Factor Receptors; Genes; Genetic; Genetic Models; Genetic Risk; Genetic study; Goals; Haplotypes; Heterozygote; Homozygote; Human; Human Genetics; Individual; Inflammation; Inflammatory; Integral Membrane Protein; Kidney; Late Onset Alzheimer Disease; Lead; Link; Longevity; Measures; Mediating; Modeling; Molecular Profiling; Mus; Outcome; Pathology; Pathway interactions; Patients; Phenotype; Physiological Processes; Process; Protein Isoforms; Public Health; Risk; Role; Senile Plaques; Serum; Slide; Symptoms; Synapses; Testing; The Jackson Laboratory; Therapeutic Intervention; Tissues; Translating; Variant; Work; age related; aging gene; anti aging; apolipoprotein E-4; base; density; frailty; genetic risk factor; high risk; human model; indexing; innovation; lifetime risk; mouse model; neuroinflammation; novel; overexpression; premature; protective effect; protective factors; sex; transcriptome sequencing; transcriptomics; β-amyloid burden

PROJECT SUMMARY Understanding how combinations of genetic risk factors influence risk for late-onset Alzheimer’s disease (LOAD) can lead to targeted strategies for therapeutic intervention. Apolipoprotein E4 (APOE4), a common variant of APOE, is the single largest genetic risk factor for developing LOAD.APOE4 status is linked to increased inflammation and higher β-amyloid burden in LOAD patients. Despite this increased genetic risk profile, APOE4 carriers do not always develop LOAD in the course of their lifetime. Several large-scale genetic studies have identified a common haplotype of the aging factor klotho that modify age of onset and reduce amyloid plaque deposition specifically in APOE4 carriers, suggesting that klotho variants can provide a protective effect against the development of LOAD by counteracting the negative effects of APOE4. In humans, klotho harbors two common missense variants (rs9536314, p.F352V; rs9527025, p.C370S). The combination of these two coding variants define the klotho V/S (KL-V/S) haplotype, which is protective against LOAD in APOE4 carriers, and the klotho F/C (KL-F/C) haplotype, which is not protective against LOAD. The overall objective of this proposal is to determine the physiological processes altered by klotho as an APOE4-specific protective factor in LOAD using a set of recently-created mouse models harboring combinations of relevant human variants in both klotho and APOE. Our central hypothesis is that the protective KL-V/S haplotype will significantly delay age-dependent inflammation and amyloid deposition while the reference KL-F/C haplotype will fail to attenuate these hallmark LOAD pathologies. We will assess multiple LOAD-relevant outcomes to validate and characterize this klotho- APOE genetic interaction with three specific aims: (1) Determine the effects of klotho haplotypes on age-related frailty and klotho isoform levels in blood and CSF in mice; (2) Determine changes in LOAD hallmark pathologies driven by the interaction between klotho and APOE alleles in mice; and (3) Identify molecular signatures shared in human LOAD stratified by klotho haplotype and the novel klotho mouse models. The outcome of this work will result in the characterization of new mouse models of human klotho haplotypes and identify the pathways which are differentially affected by klotho variants in an APOE-dependent manner. This information will provide a biological basis for the epistatic interaction observed in human genetic studies, thereby providing the necessary functional information to guide potential treatments based on KL-V/S protection for APOE4 carriers.

项目摘要 了解遗传危险因素的组合如何影响晚期阿尔茨海默氏病的风险（负载） 可以导致针对性的治疗干预策略。载脂蛋白E4（APOE4），一种常见变体 Apoe是开发负载的最大遗传危险因素。POE4状态与增加有关 负载患者的炎症和较高的β-淀粉样burnen。尽管这增加了遗传风险概况，但APOE4 运营商在一生中并不总是会发育负担。一些大规模的遗传研究已经 确定了衰老因子klotho的常见单倍型，该因子修改了发作年龄并减少淀粉样蛋白斑块 特别是在ApoE4载体中的沉积，这表明Klotho变体可以提供保护的效果 通过抵消APOE4的负面影响来发展负载。在人类中，克洛托拥有两个 常识变体（RS9536314，P.F352V； RS9527025，P.C370S）。这两个编码的结合 变体定义了Klotho V/S（KL-V/S）单倍型，该单倍型可免受APOE4载体的载荷，并免受负载 klotho f/c（kl-f/c）单倍型，不受载荷的保护。该提议的总体目的是 确定Klotho改变的物理过程作为使用 一组最近创建的小鼠模型，它们具有Klotho和Klotho中相关人类变体的组合 apoe。我们的中心假设是受保护的KL-V/S单倍型将显着延迟年龄依赖性 引用KL-F/C单倍型的炎症和淀粉样蛋白沉积将无法降低这些标志 负荷病理。我们将评估多个与负载相关的结果，以验证和表征此Klotho- 与三个特定目标的APOE遗传相互作用：（1）确定Klotho单倍型对年龄相关的影响 小鼠血液和CSF中的脆弱和klotho同工型水平； （2）确定负载标志性病理的变化 受小鼠Klotho和Apoe等位基因之间的相互作用的驱动； （3）确定共享的分子特征 在由Klotho单倍型和新型Klotho小鼠模型分层的人体负载中。这项工作的结果将 导致人类klotho单倍型的新小鼠模型的表征，并确定哪些途径 以APOE依赖性方式受Klotho变体的影响不同。此信息将提供 在人类遗传研究中观察到的上位互动的生物学基础，从而提供必要 功能信息以基于KL-V/S保护APOE4载体的保护指导潜在治疗。