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Establishing a Single-Cell Proteomic Atlas for Normal and Osteoarthritic Articular Cartilage

建立正常和骨关节炎关节软骨的单细胞蛋白质组图谱

基本信息

批准号：
10405629
负责人：
Nidhi Bhutani
金额：
$ 52.74万
依托单位：
STANFORD UNIVERSITY
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：
2021-05-17 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10405629
关键词：
Affect Animal Model Animals Antibodies Atlases Cartilage Cartilage Diseases Cells Chondrocytes Clinical Trials Cytometry D Cells Data Degenerative polyarthritis Detection Disease Disease Progression Encapsulated Event Extracellular Matrix Failure Goals Heterogeneity Homeostasis Human I-kappa B Proteins In Situ Individual Inflammation Inflammatory Joints Knowledge Label Maps Medical Molecular Pain management Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Population Proteins Proteomics Publishing Rare Earth Metals Reporting Research Resolution Resources Sampling Science Signal Pathway Stains Techniques Technology Testing Therapeutic Tissue Engineering Tissues articular cartilage cartilage regeneration cartilage repair cell type cohort drug candidate drug development inflammatory marker inhibitor insight mouse model novel pre-clinical receptor regeneration potential regenerative regenerative cell response senescence single-cell RNA sequencing small molecule inhibitor success therapeutic evaluation transcriptome sequencing transcriptomics

项目摘要

Abstract Although multiple pathways and targets have been proposed for OA treatment, the rate of drug failure in clinical trials has been astoundingly high. The reasons for the limited success include the late detection of the disease and a lack of understanding of the molecular heterogeneity between patients. In this proposal, we aim to capitalize on the newly developed single-cell proteomic technique, mass cytometry (CyTOF) that allows detection of 40-80 proteins simultaneously in single cells, with the aim of identifying the diverse cellular subpopulations in OA cartilage. Although cartilage is a relatively simple tissue, with a single cell type being encapsulated in its secreted extracellular matrix (ECM), the variable degree of degeneration associated with each OA patient suggests that understanding this tissue (and other joint tissues) at a single cell level can provide novel insights into both OA pathology and patient heterogeneity. This will compliment single-cell transcriptomic data, with the additional advantage that the proteomic snapshot can also identify active signaling pathways in the identified subpopulations. The single-cell proteomic approach is especially pertinent in robustly identifying rare cell populations that are difficult to discern from RNA-sequencing data. In this proposal, we will establish single cell profiles of a large cohort of OA cartilage samples using a refined panel of rare earth metal labeled antibodies in Aim1 to identify distinct subpopulations in OA cartilage. In aim 2, we will test if the modulation of two newly identified rare subpopulations would be therapeutic in a mouse model of post-traumatic OA as well as follow their dynamics with disease progression. In Aim 3, we will analyze how drug treatments affect the cartilage subpopulations and their crosstalk in different patients especially to discern between a uniform or heterogenous response among the patient cohort. Collectively, the proposed studies will be impactful in identifying novel regenerative and pathological cell populations in OA and testing the therapeutic potential of their modulation.

摘要