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Principal Investigator: Nidhi Bhutani
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $516,747
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
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.
Terms: <Ablation><Acceleration><Affect><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Arthroplasty><Atlases><Autoregulation><Body Tissues><Cartilage><Cartilage Diseases><Cartilaginous Tissue><Cell Body><Cell-Extracellular Matrix><Cells><Chondrocytes><Clinical Trials><Cytometry><Data><Degenerative Arthritis><Degenerative polyarthritis><Detection><Disease><Disease Progression><Disorder><Drug Therapy><Drugs><ECM><Encapsulated><Event><Extracellular Matrix><Failure><Goals><Heterogeneity><Homeostasis><Human><I-kappa B><I-kappa B Proteins><IKB><In Situ><Individual><Inflammation><Inflammatory><Joint Prosthesis Implantation><Joints><Knowledge><Label><Maps><Medical><Medication><Modern Man><Molecular><NF-Kappa B Inhibitor><NFKB Inhibitor><Osteoarthritis><Osteoarthrosis><Pain Control><Pain Therapy><Pain management><Pathogenesis><Pathogenicity><Pathologic><Pathology><Pathway interactions><Patients><Pharmaceutical Preparations><Pharmacotherapy><Physiological Homeostasis><Population><Proteins><Proteomics><Publishing><RNA Seq><RNA sequencing><RNAseq><Rare Earth Metals><Receptor Protein><Replacement Arthroplasty><Reporting><Research><Research Resources><Resolution><Resources><Sampling><Science><Signal Pathway><Staining method><Stains><Techniques><Technology><Testing><Therapeutic><Tissue Engineering><Tissues><Traumatic Arthritis><Traumatic Arthropathy><articular cartilage><bioengineered tissue><cartilage disorder><cartilage regeneration><cartilage repair><cell type><cohort><degenerative joint disease><drug candidate><drug development><drug treatment><drug/agent><engineered tissue><hypertrophic arthritis><inflammation marker><inflammatory marker><inflammatory modulation><inhibitor><insight><joint arthroplasty><joint replacement><model of animal><mouse model><murine model><novel><osteoarthritic><pain treatment><pathway><post-traumatic osteoarthritis><pre-clinical><preclinical><rare earth element><receptor><regeneration potential><regenerative><regenerative cell><regenerative potential><resolutions><response><scRNA-seq><senescence><senescent><senescent cell><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small molecular inhibitor><small molecule inhibitor><success><therapeutic evaluation><therapeutic testing><transcriptome sequencing><transcriptomic sequencing><transcriptomics>