Identifying shared and distinct cell type vulnerability across neurological diseases.

识别神经系统疾病中共有和不同的细胞类型脆弱性。

• 批准号: 10370858
• 负责人: Osama Al Dalahmah
• 金额: $ 44.55万
• 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: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370858
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Area; Autopsy; Brain; Brain region; Cell Nucleus; Cells; Clinical; Data; Data Set; Disease; Foundations; Frontotemporal Dementia; Gene Expression; Gene Expression Profile; Gene Proteins; Generations; Goals; Huntington Disease; Individual; Investigation; Knowledge; Light; Link; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Overlapping Genes; Parkinson Disease; Pathologic; Pathology; Proteomics; Publishing; Research; Research Personnel; Resolution; Resources; Signal Transduction; Small Nuclear RNA; Specific qualifier value; Standardization; Techniques; Tissues; brain tissue; cell type; data sharing; data visualization; frontotemporal lobar dementia-amyotrophic lateral sclerosis; genome wide association study; genome-wide; insight; nervous system disorder; response; transcriptome sequencing; transcriptomics

PROJECT SUMMARY A central question in neurodegeneration research is to identify type-specific changes associated with the onset and progression of neurological disease. Currently, studying alterations in cell type composition, signatures, and function in response to pathology are areas of active investigation in Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), and Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS- FTD) research. For polygenic diseases such as AD, PD, and ALS-FTD, genome-wide association, bulk tissue transcriptomics, and bulk proteomics studies have highlighted candidate loci, genes, and proteins with significant associations to pathological and clinical manifestations of diseases. However, these efforts are focused separately on each disease; thus, the major gap is a lack of studies that systematically examine tissue from the same brain regions from individuals with different neurodegenerative diseases. Here, we aim to contextualize disease-specific bulk tissue findings using cutting-edge techniques at single-cell resolution to characterize commonalities and differences in cell type-specific changes across different neurodegenerative diseases. Such cross-disease investigation is likely to shed light on each disease individually, by linking specific cell type changes to pathologies that are hallmarks for a particular neurodegenerative disease. In parallel with data generation and analysis, we also aim to create a standardized, cross-disease interactive portal for investigators to explore not only cell type-specific signatures that are associated with individual neurodegenerative diseases like AD, but also signatures that are shared between AD and other diseases. This approach will not only further our understanding of AD-specific cell type vulnerability, but also distinguish between specific and general signatures of neurodegeneration in multiple other diseases. Thus, our overall goals are not only to create a foundational data set to refine our understanding of cell type vulnerability and alteration within AD and across other neurodegenerative diseases, but also to establish a robust framework to allow external researchers to derive new disease-specific insights into cell type composition changes in neurodegeneration.

项目摘要 神经退行性研究中的一个核心问题是确定与发作相关的特定类型的变化 和神经疾病的进展。目前，研究细胞类型组成，特征和 响应病理学的功能是在阿尔茨海默氏病（AD），帕金森氏病积极研究的领域 疾病（PD），亨廷顿疾病（HD）和肌萎缩性侧索硬化 - 氟次痴呆（ALS-- FTD）研究。对于诸如AD，PD和ALS-FTD等多基因疾病，全基因组关联，散装组织 转录组学和大量蛋白质组学研究强调了候选基因座，基因和蛋白质，具有重要的 与疾病的病理和临床表现的关联。但是，这些努力是集中的 分别对每种疾病；因此，主要差距是缺乏研究的研究 来自患有不同神经退行性疾病的个体的大脑区域。在这里，我们旨在背景化 使用单细胞分辨率的尖端技术来表征疾病特异性的散装组织发现 不同神经退行性疾病的细胞类型特异性变化的共同点和差异。这样的 交叉疾病调查可能通过连接特定的细胞类型来单独阐明每种疾病 变化是特定神经退行性疾病的标志的病理。与数据并行 生成和分析，我们还旨在为调查人员创建标准化的跨疾病交互式门户 不仅探索与单个神经退行性疾病相关的细胞类型特异性特异性特征 像AD一样，也可以在AD和其他疾病之间共享的签名。这种方法不仅会进一步 我们对广告特异性细胞类型脆弱性的理解，但也区分特定和一般性和一般性 其他多种疾病中神经变性的特征。因此，我们的总体目标不仅是创造一个 基础数据集，以完善我们对AD和跨越细胞类型脆弱性和变化的理解 其他神经退行性疾病，同时也建立一个强大的框架以允许外部研究人员 将新的疾病特异性见解引入神经变性的细胞类型组成变化。