Identifying shared and distinct cell type vulnerability across neurological diseases.

项目摘要 神经变性研究的一个中心问题是确定与发病相关的类型特异性变化 和神经系统疾病的进展。目前，研究细胞类型组成、特征和 响应病理学的功能是阿尔茨海默氏病（AD）、帕金森氏病（PD）和阿尔茨海默病（AD）中积极研究的领域。 疾病（PD）、亨廷顿氏病（HD）和肌萎缩侧索硬化-额颞叶痴呆（ALS-1）。 FTD）研究。对于多基因疾病，如AD、PD和ALS-FTD，全基因组关联，大块组织 转录组学和大量蛋白质组学研究已经突出了具有显著差异的候选基因座、基因和蛋白质。 与疾病的病理和临床表现的关联。然而，这些努力的重点是 因此，主要的差距是缺乏系统地检查组织的研究， 来自不同神经退行性疾病患者的相同大脑区域。在这里，我们的目标是 使用单细胞分辨率的尖端技术， 不同神经退行性疾病中细胞类型特异性变化的共性和差异。等 交叉疾病研究可能通过将特定的细胞类型联系起来， 作为特定神经退行性疾病标志的病理变化。与数据并行 生成和分析，我们还旨在为研究人员创建一个标准化的跨疾病交互式门户网站 不仅探索与个体神经退行性疾病相关的细胞类型特异性特征， 比如AD，还有AD和其他疾病之间的共同特征。这种做法不仅将进一步 我们对AD特异性细胞类型脆弱性的认识，还要区分特异性和一般性 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内细胞类型脆弱性和改变的理解， 其他神经退行性疾病，但也建立了一个强大的框架，让外部研究人员， 获得新的疾病特异性的见解细胞类型组成的变化在神经变性。

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.