# BCCMA: Targeting Osteoarthritis Pain and Progression: Proteomics, RNASeq & Immunostaining to elucidate the immune pathotypes of OA

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2023 · —

## Abstract

The TOPP Collaborative Merit will test the central hypothesis that heterogeneity in OA pain and structural
progression is related to the “immune pathotype” of OA, which arises from the variability in the cellular and
molecular responses of bone, cartilage, and synovium to inflammation and joint mechanical environment. The
overarching Specific Aims are: Aim 1: To improve understanding of osteoarthritis (OA) pathogenesis to enable
development of targeted early treatment approaches; and Aim 2: To establish preclinical and clinical data for
new therapeutic targets to reduce pain and prevent OA progression.
This VA Merit is Project 2 of our TOPP Collaborative Merit. This Merit will use biospecimens from early and
late OA clinical cohorts prevalent in the the VA health care system to define the immune pathotypes of OA,
with the ultimate goal of using biomarkers for these pathotypes to guide care. Previous studies from our
laboratory implicate “low-grade” innate immune inflammation, and we previously identified key roles for
dysregulated activation of the complement system, mast cells, and inflammatory macrophage in the
pathogenesis of OA. In further invetigations of the cellular, transcriptional and molecular profiles of synovial
membranes from early and late OA, we observe distinct transcriptional signatures, immune cell populations,
and immune pathway activation. We hypothesize that differences in the immune cell composition and
activation states in synovium, bone and cartilage will identify “immune pathotypes” of OA, and that these
immune pathotypes will be associated with differential levels of pain, structural progression, and/or response to
treatment. In Aim 1, we propose to perform proteomic, bulk RNA-Seq, single cell RNA-Seq, and multiplex
immunostaining of human pre-OA (with Dr. Chu) and OA synovial tissues. Aim 2 will perform integrated
informatic analyses using machine learning and other approaches to identify immune pathotypes of human
pre-OA and OA. Aim 3 will determine if the immune pathotypes identified correlate with OA pain and structural
pathology in humans, and/or response to tVNS (with Dr. Humphrey) or anti-NGF (with Dr. Nakamura) in mice.
Success of the herein proposed studies and of our overarching TOPP Collaborative Merit proposal would
transform our understanding of the pathobiology of OA, and could lead to more effective approaches to treat
pain and the first ever disease-modifying therapy for OA.

## Key facts

- **NIH application ID:** 10590409
- **Project number:** 1I01CX002523-01A1
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** William H Robinson
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10590409

## Citation

> US National Institutes of Health, RePORTER application 10590409, BCCMA: Targeting Osteoarthritis Pain and Progression: Proteomics, RNASeq & Immunostaining to elucidate the immune pathotypes of OA (1I01CX002523-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10590409. Licensed CC0.

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