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.

抽象的 阿尔茨海默氏病（AD）中的一个核心问题是细胞类型特异性变化的作用 疾病的发作和进展。全基因组关联研究已经确定了与AD相关的基因 最近的大规模转录组和蛋白质组学研究强调了 候选基因和蛋白质与AD的病理和临床表现有显着关联。 总之，这些遗传和分子研究已经实现了神经元，星形胶质细胞和小胶质细胞作为关键 广告发病机理和认知能力下降的参与者。但是，这些遗传和验尸研究 无法解析细胞类型表达式轮廓的变化是细胞自主的程度，而不是相反 成为其他细胞类型变化的下游效应。为了解决这个问题，我们提出了创新的 混合体外共培养方法，以了解具有变化的供体的细胞类型的影响 AD病理学和/或AD痴呆症对具有或没有认知的个体得出的细胞类型 衰落或病理。我们使用宗教成员的诱导多能干细胞（IPSC）线 订单研究/记忆和老化项目（ROSMAP），我们为其提供了详细的病理，临床，全部 基因组测序和验尸后分子数据。我们有关这些单一培养的初步数据 供体线在体外和验尸后蛋白质组学之间表现出高度的一致性。 和蛋白质疗法数据。这使我们能够将我们的体外发现直接锚定在患者表型和 验尸后脑组织数据的分析。基于此锚定，我们的方法是“混合和匹配”单元格 来自不同IPSC线的类型特异性培养物，从而使我们能够解散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A的细胞从A的细胞中诱导非自主 具有不同遗传背景，病理学和事前认知轨迹的供体。重要的是，我们 在体外寻找配置的，多基广告相关的信号，这些信号存在于不同的供体之间 遗传背景，而不是直接表征特定变体对细胞类型的影响。给出 AD遗传风险变体的高度多因素性质，我们认为这种方法可以实现强大 鉴定与该疾病相关的收敛细胞类型特异性作用。