# BLRD Research Career Scientist Award Application

> **NIH VA IK6** · JESSE BROWN VA MEDICAL CENTER · 2024 · —

## Abstract

Rheumatoid arthritis (RA) is the most common autoimmune disease which affects 2.5 million people in the US,
many of which are VA military personnel. One in four veterans has arthritis (25.6%), compared to one in five
civilians. RA is a chronic, disabling autoimmune disease in which the body attacks its tissues. As RA progresses,
performing simple daily activities becomes increasingly difficult for patients suffering from the disease. Presently,
there is no cure for RA and up to 50% of patients diagnosed with RA do not respond to current treatments or
lose their responsiveness over time. Findings that lead to new therapy will benefit the VA personnel by reducing
the cost of medical and surgical care; in addition to the secondary RA complications including depression,
cardiovascular disease, and psychosocial stress. Consequently, effective RA therapy will improve the pain & the
life quality of veterans.
My laboratory focuses on identifying the mechanisms that lead to joint inflammation, immunometabolism, bone
erosion in immune cells, and their ability to cross-regulate joint vascularization. Our research at Jesse Brown VA
Medical Center has focused on discovering a unique TLR7 endogenous ligand in rheumatoid arthritis (RA)
synovial fluid exosomes, which exclusively bind to myeloid TLR7. The TLR7 endogenous ligand, miR-Let7b,
remodels the naïve RA myeloid cells into inflammatory MΦs and erosive osteoclasts. Intriguingly, we show that
IRAK4 inhibitor therapy disrupts miR-Let7b-mediated inflammatory and metabolic imprints in RA macrophage,
fibroblasts, and preclinical models in part via HIF1α and cMYC downregulation. This work is very relevant to the
Veteran's health, as the IRAK4 inhibitor is at phase 2 for RA therapy and could reduce the cost of medical and
surgical care and improve the life quality of the veterans.
Currently, we aim to identify novel therapeutic targets for patients that do not respond to biotherapies. As such,
we have uncovered novel pathways that can markedly alleviate pannus formation by intercepting the unique
networks interconnecting RA inflammatory macrophages to joint neovasculature via metabolic reprogramming.
Unlike the current RA standard of care, the mechanism of action is not limited to a specific inflammatory factor
and its function will impact multiple cell types in the RA pannus and their metabolic crosstalk. We are proposing
a unique way of negating RA pannus formation which has not been examined previously.
Intriguingly, we are examining the inflammatory & metabolic profiles of RA circulating blood and synovial tissue
macrophages in response to an identified endogenous factor to delineate if blockade of hypermetabolic activity
will reverse the inflammatory phenotype by RNA-sequencing and CyTOF. We are also uncovering the impact of
the identified synovial fluid endogenous factor on endothelial cell metabolic reprogramming and their cross-
regulation with RA macrophages by carbon isotype labeling for tracing glucose,...

## Key facts

- **NIH application ID:** 10804882
- **Project number:** 1IK6BX006474-01
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** SHIVA SHAHRARA
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2028-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804882

## Citation

> US National Institutes of Health, RePORTER application 10804882, BLRD Research Career Scientist Award Application (1IK6BX006474-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10804882. Licensed CC0.

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