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.

概括 阿尔茨海默氏病 (AD) 普遍存在且令人衰弱，目前尚无真正有效的治疗方法。 全基因组关联研究发现了散发性迟发性 AD 的风险变异，但 导致这种风险的机制仍然未知，其中两个 SAD 变体的风险最高。 载脂蛋白 E (APOE) 和 ATP 结合盒与 AD 发展相关 转运蛋白 A7 (ABCA7)，两者都参与脂质代谢。 证明 APOE (APOE4) 的 E4 等位基因具有细胞类型特异性效应，包括 脂质代谢的改变，但下游途径仍然存在重要问题 重要的是，我们不知道 APOE4 诱导的变化如何相互作用。 与衰老相关的压力会导致迟发性疾病，而关于 ABCA7 是如何导致的，我们知之甚少。 等位基因会导致 AD 风险增加，我们建议使用系统生物学方法来发现。 这些 AD 风险途径，响应 NIH 的 NOT-AG-18-052，指定 “源自人类 AD 诱导多能干细胞的脑神经细胞的系统生物学” 我们的方法使用诱导多能的多组学分析。 两种风险变异（APOE4 或 ABCA7 过早）同基因的干细胞 (iPSC) 系 终止（PTC），然后可以使用无偏性分化为不同的细胞类型。 通过这种方法，我们将揭示 AD 风险等位基因如何改变细胞的信号传导、新陈代谢和状态， 它们如何影响复杂培养物中的单个细胞以及细胞与细胞的相互作用，以及它们如何 在目标 1 中，我们将深入描述细胞对急性应激的反应。 神经元、星形胶质细胞、小胶质细胞和周细胞二维培养模型中的 APOE4 和 ABCA7 PTC， 与同基因 iPSC 系区分开来，检查代谢和翻译后的变化 我们将使用先进的网络优化方法来进行蛋白质修饰（PTM）。 整合不同的数据并揭示链接在一起的分子相互作用网络 在目标 2 中观察到的个体组学变化，我们研究了风险改变的途径。 使用空间解析 PTM- 影响 3D 培养模型中细胞间相互作用的等位基因 在目标 3 中，我们将蛋白质组学和代谢组学/脂质组学和因果计算模型。 在 3D 中检查风险变异与环境和细胞压力源的交叉点 每个目标都包括严格的体外假设测试和检验 尸检样本。