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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

项目概要了解遗传风险因素的组合如何影响晚发性阿尔茨海默病 (LOAD) 的风险可以导致治疗干预的针对性策略。载脂蛋白 E4（APOE4）是一种常见的变体。 APOE 是发生 LOAD 的最大的单一遗传风险因素。APOE4 状态与增加有关 LOAD 患者的炎症和较高的 β-淀粉样蛋白负荷尽管遗传风险增加，但 APOE4 仍然存在。一些大规模的遗传学研究表明，携带者并不总是在一生中出现 LOAD。确定了衰老因子 klotho 的常见单倍型，它可以改变发病年龄并减少淀粉样斑块特别是在 APOE4 载体中沉积，表明 klotho 变体可以提供针对 APOE4 载体的保护作用通过抵消 APOE4 的负面影响来发展 LOAD 在人类中，klotho 具有两种。常见错义变体（rs9536314，p.F352V；rs9527025，p.C370S）这两种编码的组合。变体定义了 klotho V/S (KL-V/S) 单倍型，该单倍型对 APOE4 携带者中的 LOAD 具有保护作用，并且 klotho F/C (KL-F/C) 单倍型，对 LOAD 没有保护作用该提案的总体目标是确定 klotho 改变的生理过程作为 LOAD 中的 APOE4 特异性保护因子，使用一组最近创建的小鼠模型，其中包含 klotho 和 klotho 中相关人类变异的组合 APOE。我们的中心假设是保护性 KL-V/S 单倍型将显着延迟年龄依赖性。炎症和淀粉样蛋白沉积，而参考 KL-F/C 单倍型将无法减弱这些特征我们将评估多种与 LOAD 相关的结果，以验证和表征这一 klotho- APOE 遗传相互作用具有三个具体目标：（1）确定 klotho 单倍型对年龄相关的影响小鼠血液和脑脊液中的虚弱和 klotho 亚型水平； (2) 确定 LOAD 标志病理学的变化；由小鼠中 klotho 和 APOE 等位基因之间的相互作用驱动；(3) 识别共享的分子特征；在按 klotho 单倍型和新型 klotho 小鼠模型分层的人类 LOAD 中，这项工作的结果将是。导致人类 klotho 单倍型的新小鼠模型的表征，并确定了影响人类 klotho 单倍型的途径以 APOE 依赖性方式受到 klotho 变体的不同影响。此信息将提供一个人类遗传学研究中观察到的上位相互作用的生物学基础，从而提供了必要的功能信息指导基于 KL-V/S 保护的 APOE4 携带者的潜在治疗。