The effects of Alzheimer's disease risk genes on metabolism and signaling across cell types

阿尔茨海默病风险基因对跨细胞类型代谢和信号传导的影响

• 批准号: 10524301
• 负责人: Ernest Fraenkel
• 金额: $ 394.43万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 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/10524301
• 关键词: ATP-Binding Cassette Transporters; Affect; Aging; Algorithms; Alleles; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; American; Amyloid beta-Protein; Apolipoprotein E; Astrocytes; Automobile Driving; Autopsy; Behavioral; Big Data; Binding; Blood - brain barrier anatomy; Brain; Cell Communication; Cell Line; Cell physiology; Cells; Cellular Stress; Complex; Computer Analysis; Computer Models; Data; Development; Disease; Etiology; Future; Genes; Genetic; Genotype; Human; In Vitro; Individual; Inflammatory; Late Onset Alzheimer Disease; Late-Onset Disorder; Lead; Link; Lipids; Metabolic; Metabolic stress; Metabolism; Methods; Microglia; Modeling; Neurons; Onset of illness; Organoids; Outcome; Oxidative Stress; Pathogenicity; Pathologic; Pathway interactions; Patients; Pericytes; Phase; Phenotype; Population; Post-Translational Protein Processing; Proteomics; Recording of previous events; Regulatory Pathway; Research Priority; Risk; Sampling; Serum; Signal Pathway; Signal Transduction; Small Nuclear RNA; Stress; Systems Biology; Testing; Therapeutic; Tissues; United States National Institutes of Health; Variant; Work; acute stress; base; causal model; cell type; design; disorder risk; effective therapy; environmental stressor; genetic risk factor; genome wide association study; high risk; induced pluripotent stem cell; lipid metabolism; lipidomics; metabolomics; multiple omics; neurovascular unit; predictive modeling; premature; rare variant; response; risk variant; stressor; three dimensional cell culture

Summary Alzheimer's disease (AD) is pervasive and debilitating, with no truly effective treatments. Genome wide association studies have found risk variants for sporadic, late-onset AD, but the mechanisms driving this risk are still unknown. Two of the sAD variants with the highest association with development of AD are in Apolipoprotein E (APOE) and ATP-binding cassette transporter A7 (ABCA7), both of which are involved in lipid metabolism. Our prior work demonstrates that the E4 allele of APOE (APOE4) has cell type specific effects, including alterations in lipid metabolism, but important questions remain about the downstream pathways affected by this allele. Critically, we do not know how APOE4-induced changes interact with aging-related stress, leading to late-onset disease. Even less is known about how ABCA7 alleles lead to increased risk of AD. We propose to use a systems biology approach to discover these AD-risk pathways, responding to NOT-AG-18-052 from the NIH, which designates “systems biology of brain neural cells derived from human AD induced pluripotent stem cells” as a high-priority research topic. Our approach uses multi-omic analysis of induced pluripotent stem cell (iPSC) lines that are isogenic for two risk variants, APOE4 or ABCA7 premature termination (PTC), which can then be differentiated into diverse cell types. Using an unbiased approach, we will reveal how AD-risk alleles alter signaling, metabolism, and states of the cells, how they affect individual cells as well as cell-cell interactions in complex cultures, and how they alter cellular responses to acute stress. In Aim 1 we will deeply characterize the effects of APOE4 and ABCA7 PTC in 2D culture models of neurons, astrocytes, microglia and pericytes, differentiated from isogenic iPSC lines, examining changes in metabolism and post-translational modifications (PTMs) of proteins. We will use advanced network optimization methods to integrate the disparate data and to uncover molecular interaction networks that link together changes observed in the individual omics. In Aim 2, we investigate the pathways altered by risk alleles that influence cell-cell interactions in 3D culture models, using spatially-resolved PTM- proteomics and metabolomics/lipidomics and causal computational models. In Aim 3, we will examine the intersection of risk variant with environmental and cellular stressors in the 3D culture models. Each aim includes rigorous testing of hypotheses in vitro and by examination of postmortem samples.

总结 阿尔茨海默氏病（AD）是普遍的和衰弱的，没有真正有效的治疗。 全基因组关联研究已经发现了散发性迟发性AD的风险变体，但 导致这种风险的机制仍然未知。其中两种sAD变体具有最高的 与AD发生相关的是载脂蛋白E（APOE）和ATP结合盒 转运蛋白A7（ABCA 7），两者都参与脂质代谢。我们以前的工作 证明APOE的E4等位基因（APOE 4）具有细胞类型特异性效应，包括 脂质代谢的改变，但重要的问题仍然是关于下游途径 受这个等位基因的影响关键是，我们不知道APOE 4诱导的变化如何与 与衰老有关的压力导致迟发性疾病关于ABCA 7是如何 等位基因导致AD风险增加。我们建议使用系统生物学方法来发现 这些AD风险通路，响应NIH的NOT-AG-18-052，指定 “源自人AD诱导的多能干细胞的脑神经细胞的系统生物学”， 高优先级的研究课题。我们的方法使用多组学分析诱导多能 对于两种风险变体APOE 4或ABCA 7早熟是等基因的干细胞（iPSC）系 终止（PTC），然后可以分化成不同的细胞类型。用无偏差 方法，我们将揭示AD风险等位基因如何改变信号，代谢和细胞状态， 它们如何影响单个细胞以及复杂培养物中的细胞间相互作用，以及它们如何 改变细胞对急性应激的反应在目标1中，我们将深入描述 神经元、星形胶质细胞、小胶质细胞和周细胞的2D培养模型中的APOE 4和ABCA 7 PTC， 从同基因iPSC系分化，检查代谢和翻译后 蛋白质修饰（PTM）。我们将使用先进的网络优化方法， 整合不同的数据，揭示连接在一起的分子相互作用网络 在个体组学中观察到的变化。在目标2中，我们研究了风险改变的途径 在3D培养模型中影响细胞-细胞相互作用的等位基因，使用空间分辨的PTM- 蛋白质组学和代谢组学/脂质组学和因果计算模型。在目标3中，我们 检查风险变量与3D环境和细胞应激源的交叉点 文化模式每个目标都包括严格的体外假设测试， 尸体样本