# An integrative study of circulating leukocyte composition, epigenetic patterns,  and functional consequences in knee osteoarthritis

> **NIH NIH K08** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2021 · $158,981

## Abstract

Project Summary / Abstract
My previous research in epigenetics and clinical training as a rheumatology fellow have prepared me well for a
future career as a physician scientist. The K08 proposal described herein will allow me the necessary protected
time and mentoring to expand my skills and achieve my primary goals of becoming leader in the field of
osteoarthritis (OA) epigenetics. I will participate in formal coursework with a particular focus on bioinformatics,
statistics, and research communication at the University of Oklahoma Health Sciences Center. I will expand my
presentation skills through both didactic training and presentation of my research findings. My career
development will be greatly advanced by my appointment as an Oklahoma Shared Clinical and Translational
Resources Scholar, as well as regular meetings with my primary mentor and advisory committee.
My research during this pivotal period will focus on OA, a chronic, debilitating musculoskeletal disease affecting
40% of US adults over the age of 70. Understanding the mechanisms of gene-environmental interaction and the
contributions of extraarticular tissues to OA are key to the development of clinical biomarkers and therapeutic
agents. I have published data showing significantly altered DNA methylation patterns in OA cartilage and
subchondral bone, and have preliminary data from peripheral blood mononuclear cells of OA patients
demonstrating remarkably consistent epigenetic dysregulation of several immune-related pathways. Based on
these data, I hypothesize that OA is a disease characterized by low-level systemic inflammation, associated with
dysregulated epigenomes that alter gene transcription, leading to disease pathogenesis.
To evaluate this, I will recruit knee OA patients at risk of radiographic progression and perform serial blood
draws and knee X-rays for later analysis. I will determine if changes in circulating inflammatory cell populations
and/or their response to stimulation are present in knee OA patients compared to both healthy and rheumatoid
arthritis controls (Aim 1), and examine whether patterns in inflammatory cell composition are predictive of
radiographic OA progression over time, using state-of-the-art cyTOF analysis. I will then confirm an altered
DNA methylation pattern using banked DNA from a large OA cohort (Aim 2a). Subsequently, I will study DNA
methylation and gene transcription in leukocyte subsets: CD4+, CD8+, and monocyte cells (Aim 2b). Finally, I
will use a novel, targetable dCas9-TET1 fusion protein to evaluate the functional consequences of specific DNA
demethylation events I previously identified in my OA cartilage work (Aim 3).
Discoveries achieved by these aims will form the preliminary data for strong R01 applications to confirm novel
diagnostic biomarkers and develop new therapeutic strategies to treat this devastating disease. If successful, I
will provide the first data regarding circulating OA inflammatory cell subpopulations. Leveragi...

## Key facts

- **NIH application ID:** 10210358
- **Project number:** 5K08AR070891-06
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Matlock Jeffries
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $158,981
- **Award type:** 5
- **Project period:** 2020-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210358

## Citation

> US National Institutes of Health, RePORTER application 10210358, An integrative study of circulating leukocyte composition, epigenetic patterns,  and functional consequences in knee osteoarthritis (5K08AR070891-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10210358. Licensed CC0.

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