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Single-Cell Functional Proteomics Study of Neurodegeneration in Alzheimer's Disease

阿尔茨海默病神经退行性变的单细胞功能蛋白质组学研究

基本信息

批准号：
10191268
负责人：
Jun Wang
金额：
$ 43.86万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10191268
关键词：
Address Aging Algorithms Alzheimer&apos s Disease Alzheimer&apos s disease pathology Amyloid Amyloid deposition Antibodies Apoptosis Area Bar Codes Bioinformatics Biological Assay Biological Markers Biological Process Biomedical Research Brain Brain region Cell Line Cell physiology Cells Characteristics Cleaved cell Clinic Clinical Complement Corpus striatum structure Cytometry DNA Data Dementia Development Disease Progression Drug Targeting Enzymes Foundations Gene Expression Growth Heterogeneity Hippocampus (Brain)Image Immunofluorescence Immunologic Impaired cognition In Situ In Vitro Individual Investigation Label Laboratories Measurement Measures Membrane Proteins Memory Loss Methods Molecular Mouse Cell Line Mus Nerve Degeneration Neurofibrillary Tangles Neuronal Injury Neurons Oligonucleotides Outcome Pathogenesis Pattern Positron-Emission Tomography Protein Analysis Proteins Proteome Proteomics Public Health Research Resistance Signal Transduction Signaling Protein Specimen Stains Structure Surface Surveys Techniques Technology Testing Therapeutic Time Tissue Preservation Validation abeta toxicity antibody detection base biomarker development biomarker identification brain cell cell type clinical Diagnosis cohort economic impact fluoro jade health care economics in vivo in vivo imaging innovation innovative technologies microPET microchip molecular marker mouse model multiplex detection neuropathology new technology novel pre-clinical protein profiling radiotracer single cell analysis single cell proteins single cell sequencing single-cell RNA sequencing success therapeutic target tool transcription factor transcriptome transcriptomics

项目摘要

Summary Alzheimer’s disease (AD) and other dementias are a looming public health crisis in the US which is expected to generate catastrophic healthcare and economic impacts over the next decades. Despite enormous efforts made in AD research, current treatments provide only marginal benefits in the clinic. Many studies on early AD have found certain regions of the brain are more vulnerable to degeneration than others. But the investigation into the molecular mechanisms behind such selective degeneration is challenging and is hampered by the complexity of cellular machinery and heterogeneity. Although the sequencing based single-cell transcriptomics can address this challenge to certain degree, the conclusions usually still need validation at the protein level. Since most cellular functions, drug targets, and clinical diagnosis are based on protein signaling and biomarkers, the development of a counterpart functional proteomics technology would be beneficial to provide another perspective more directly relevant to therapeutics. Besides, surveying a large panel of proteins at the omics level is necessary since the cohort of proteins critical to AD pathogenesis remains elusive. In this project, we will develop a single-cell functional proteomics tool that could complement single-cell sequencing by measuring 300 critical proteins relevant to neurodegeneration. This novel technology will increase the coverage of functional proteome by 10-100 times over prevailing technologies, and it will take biomedical research broadly to a new level. This tool, in tandem with in vivo microPET imaging and in vitro specimen imaging, will facilitate identification of the biomarkers and regulatory networks pertinent to the subpopulations of brain cells that are vulnerable or resistant to neurodegeneration and amyloid beta toxicity. The proposed aims are (1) Establish single-cell reiterative MIST technology for analyzing 300 intracellular and surface proteins, and optimize the assay conditions by testing on a mouse cell line, and (2) Determine the molecular markers and regulatory networks of vulnerable versus resistant brain cells using single-cell reiterative MIST technology, microPET and degeneration imaging on an AD mouse model. The success of this project will generate innovative technology and methods that enable deep investigation of AD pathogenesis from a new, clinically important perspective, and it will lay the foundation for further brain-wide study of AD development and identification of drug targets.

概括阿尔茨海默病 (AD) 和其他痴呆症是美国迫在眉睫的公共卫生危机，预计将在未来几十年内产生灾难性的医疗保健和经济影响。尽管付出了巨大的努力在 AD 研究中，目前的治疗方法在临床上仅提供边际效益。许多关于早期 AD 的研究表明发现大脑的某些区域比其他区域更容易退化。但经调查这种选择性变性背后的分子机制具有挑战性，并且受到复杂性的阻碍细胞机制和异质性。尽管基于测序的单细胞转录组学可以解决尽管这一挑战在一定程度上受到了挑战，但结论通常仍需要在蛋白质水平上进行验证。由于大多数细胞功能、药物靶点和临床诊断基于蛋白质信号传导和生物标志物，开发相应的功能蛋白质组学技术将有利于提供另一种与治疗学更直接相关的观点。此外，在组学水平上调查大量蛋白质这是必要的，因为对 AD 发病机制至关重要的一组蛋白质仍然难以捉摸。在这个项目中，我们将开发一种单细胞功能蛋白质组学工具，可以通过测量 300 来补充单细胞测序与神经变性相关的关键蛋白质。这项新技术将增加功能的覆盖范围蛋白质组是现有技术的 10-100 倍，它将把生物医学研究广泛地推向一个新的水平等级。该工具与体内 microPET 成像和体外样本成像相结合，将有助于识别与脆弱或易受攻击的脑细胞亚群相关的生物标志物和调控网络抵抗神经变性和β淀粉样蛋白毒性。拟议的目标是（1）建立单细胞用于分析 300 种细胞内和表面蛋白并优化测定的重复 MIST 技术通过在小鼠细胞系上进行测试来确定条件，以及（2）确定分子标记和调控网络使用单细胞重复 MIST 技术、microPET 和变性来比较脆弱与抵抗的脑细胞 AD 小鼠模型上的成像。该项目的成功将产生创新技术和方法这使得能够从一个新的、临床上重要的角度深入研究 AD 发病机制，并将奠定为进一步研究 AD 发展和药物靶点识别奠定了基础。