Spatial analysis of regional, cell type and molecular hallmarks of Alzheimer's disease

阿尔茨海默病的区域、细胞类型和分子标志的空间分析

基本信息

批准号：
10375363
负责人：
Ed Lein
金额：
$ 178.48万
依托单位：
ALLEN INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10375363
关键词：
Address Adult Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Amyloid beta-Protein Precursor Area Brain Brain region Cell Nucleus Cells Classification Clinical Data Deposition Disease Progression Fluorescent in Situ Hybridization Frequencies Future Gene Expression Gene Expression Profiling Generations Genes Genetic Transcription Goals Human Immunohistochemistry In Situ Hybridization Link Maps Measures Methods Molecular Nerve Degeneration Neuroglia Output Pathogenesis Pathologic Pathway interactions Phase Population Population Analysis Protein Analysis Proteins RNA RNA analysis Resistance Resolution Severities Severity of illness Standardization Technology Tissues Work aged aging brain base brain tissue cell type cellular targeting cholinergic neuron cohort data acquisition data analysis pipeline design epigenomics excitatory neuron hyperphosphorylated tau neuropathology progressive neurodegeneration protein aggregation protein biomarkers protein expression spatial relationship transcriptome transcriptomics

项目摘要

ABSTRACT (PROJECT 3) The molecular mechanisms underlying cellular vulnerability in Alzheimer’s disease are unclear. The objective of this project is to clarify the molecular mechanisms responsible for select cell vulnerability and pathogenesis by applying spatial methods for highly multiplexed RNA and protein analysis in Alzheimer’s-affected tissue sections. We will optimize and standardize platforms for multiplexed fluorescence in situ hybridization (mFISH) to examine AD-linked gene sets derived from single nucleus transcriptome analysis, as well as immunohistochemistry (IHC) to examine pathological protein markers in the context of cell type populations in intact human brain tissue. These methods will then be applied to Alzheimer’s disease tissues from brain regions affected in different levels of disease severity to understand 1) the spatial organization of transcriptomically-defined cell types in these brain regions and changes in this organization with disease severity (e.g. selective vulnerability or proliferation), 2) molecular pathways disrupted in Alzheimer’s disease in the context of specific cell types, and 3) the relationship between these affected cell types and the markers of Alzheimer’s pathology, such as amyloid precursor protein and hyperphosphorylated tau. These data generated by mFISH and IHC together will provide a high-resolution map of the cellular and molecular consequences of clinically typical Alzheimer’s disease and an enhanced view of Alzheimer’s pathology, as well as a powerful technology platform for future analyses of larger and more varied cohorts.

摘要（项目 3）阿尔茨海默病细胞脆弱性的分子机制尚不清楚。该项目的目的是阐明导致选择细胞脆弱性和发病机制的分子机制应用空间方法对受阿尔茨海默病影响的组织进行高度多重 RNA 和蛋白质分析我们将优化和标准化多重荧光原位杂交 (mFISH) 平台。检查源自单核转录组分析的 AD 相关基因集，以及免疫组织化学 (IHC) 用于检查细胞类型群体背景下的病理蛋白标记然后，这些方法将应用于来自大脑的阿尔茨海默病组织。受不同疾病严重程度影响的区域，以了解 1) 的空间组织这些大脑区域中转录组定义的细胞类型以及该组织因疾病而发生的变化严重程度（例如选择性脆弱性或增殖），2) 阿尔茨海默氏病的分子途径被破坏特定细胞类型的背景，以及 3) 这些受影响的细胞类型与标记物之间的关系阿尔茨海默病的病理学，例如淀粉样蛋白前体蛋白和过度磷酸化的 tau 蛋白这些数据生成。 mFISH 和 IHC 共同提供的细胞和分子结果的高分辨率图谱临床上典型的阿尔茨海默病和阿尔茨海默病病理学的增强观点，以及强大的用于未来对更大、更多样化的群体进行分析的技术平台。