Identifying cell type-specific autonomous and non-autonomous interactions in AD

识别 AD 中细胞类型特异性的自主和非自主相互作用

• 批准号: 10446168
• 负责人: Vilas Menon
• 金额: $ 256.74万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446168
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Astrocytes; Autopsy; Biological; Biological Assay; Biological Models; Candidate Disease Gene; Cell Line; Cell Nucleus; Cells; Clinical; Clinical Data; Coculture Techniques; Cognitive; DNA Sequence Alteration; Data; Dementia; Disease; Disease Progression; Foundations; Funding; Future; Gene Expression; Gene Proteins; Genes; Genetic; Genetic Risk; Genome engineering; Human; Impaired cognition; In Vitro; Individual; Induced pluripotent stem cell derived neurons; Intervention; Lead; Link; Memory; Microglia; Molecular; Nature; Nerve Degeneration; Neuroglia; Neurons; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Proteomics; Role; Signal Transduction; Small Nuclear RNA; System; Tissues; Validation; Variant; base; brain tissue; cell type; combinatorial; genetic risk factor; genetic variant; genome sequencing; genome wide association study; induced pluripotent stem cell; innovation; member; mouse model; polygenic risk score; religious order study; risk variant; single-cell RNA sequencing; transcriptome sequencing; transcriptomics; whole genome

ABSTRACT A central question in Alzheimer's Disease (AD) is the role of cell type-specific changes associated with the onset and progression of the disease. Genome-wide association studies have identified genes linked to AD, and recent large-scale transcriptomic and proteomic studies of post-mortem brain tissue have highlighted candidate genes and proteins with significant associations to pathological and clinical manifestations of AD. Together, these genetic and molecular studies have implicated neurons, astrocytes, and microglia as key players in AD pathogenesis and cognitive decline. However, these genetic and post-mortem profiling studies cannot resolve the degree to which a change in cell type expression profile is cell autonomous, as opposed to being a downstream effect of changes in other cell types. To tackle this question, we propose an innovative mixed in vitro co-culture approach to understand the effects of cell types from donors with variations in AD pathology and/or AD dementia on cell types derived from individuals with or without cognitive decline or pathology. We use induced pluripotent stem cell (iPSC) lines from members of the Religious Order Study/Memory and Aging Project (ROSMAP), for whom we have detailed pathological, clinical, whole- genome sequencing, and post-mortem molecular data. Our preliminary data on monocultures from these donor lines shows a high degree of concordance between in vitro and post-mortem transcriptomic, proteomic, and proteinopathic data. This allows us to anchor our in vitro findings directly to patient phenotypes and analyses of post-mortem brain tissue data. Based on this anchoring, our approach is to “mix and match” cell type-specific cultures from different iPSC lines, thereby allowing us to disentangle which cell type-specific changes in vitro are likely cell type autonomous, and which are induced non-autonomously by cells from a donor with a different genetic background, pathology, and ante-mortem cognitive trajectory. Importantly, we look for conserved, polygenic AD-associated signals in vitro that are present across donors with varied genetic backgrounds, as opposed to directly characterizing the effect of a specific variant on cell type. Given the highly multifactorial nature of AD genetic risk variants, we believe this approach allows for robust identification of convergent cell type-specific effects associated with the disease.

摘要 阿尔茨海默病（AD）的一个中心问题是与阿尔茨海默病（AD）相关的细胞类型特异性变化的作用。 疾病的发生和发展。全基因组关联研究已经确定了与AD相关的基因， 最近对死后脑组织的大规模转录组学和蛋白质组学研究强调， 与AD的病理和临床表现有显著关联的候选基因和蛋白质。 总之，这些遗传和分子研究涉及神经元，星形胶质细胞和小胶质细胞作为关键 参与AD发病机制和认知能力下降。然而，这些基因和死后分析研究 不能分辨细胞类型表达谱的变化是细胞自主的程度， 成为其他细胞类型变化的下游效应。为了解决这个问题，我们提出了一个创新的 混合体外共培养方法，以了解来自供体的细胞类型的影响， AD病理学和/或AD痴呆对来自有或没有认知能力的个体的细胞类型的影响 衰退或病理学。我们使用来自宗教团体成员的诱导多能干细胞（iPSC）系， 为了研究/记忆和衰老项目（ROSMAP），我们有详细的病理，临床，整体- 基因组测序和死后的分子数据我们对这些单一栽培的初步数据 供体系在体外和死后转录组学、蛋白质组学 和蛋白质病理学数据。这使我们能够锚我们的体外研究结果直接对患者的表型， 尸检脑组织数据的分析基于这种锚定，我们的方法是“混合和匹配”单元格 来自不同iPSC系的类型特异性培养物，从而使我们能够解开哪种细胞类型特异性 体外变化可能是细胞类型自主的，并且由来自细胞的细胞非自主诱导。 具有不同遗传背景、病理学和生前认知轨迹的供体。重要的是我们 在体外寻找保守的多基因AD相关信号，这些信号存在于具有不同 遗传背景，而不是直接表征特定变体对细胞类型的影响。给定 AD遗传风险变异的高度多因素性质，我们相信这种方法可以实现稳健的 鉴定与疾病相关的会聚细胞类型特异性效应。