# IRAK4 and Systemic Lupus Erythematosus

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $398,750

## Abstract

Systemic lupus erythematosus (SLE) is a devastating autoimmune disease that affects 5 million people
worldwide. Treatment of lupus patients with corticosteroids, antimalarial, or anti-inflammatory drugs have
limited efficacy. FDA-approved Benlysta, a human antibody against B-lymphocyte stimulator, decreased
disease severity in SLE patients, but caused significant side effects (infections, nausea, diarrhea, fever) and
was ineffective in African Americans. Thus, there is an urgent need to develop new therapeutic strategies for
lupus. Accumulating evidence demonstrates the involvement of Toll-like receptors (TLRs) in SLE, and targeting
TLRs is a promising strategy, but the role of TLR signaling pathways in SLE is incompletely understood.
Several TLRs (TLR2, TLR4, TLR7, TLR9) are involved in lupus, indicating that targeting one TLR would leave
signaling pathways initiated by other TLRs unaffected. This redundancy dictates the need for a more global
targeting of common SLE-promoting TLR pathways for intervention. Since IRAK4 is a critical kinase that is
regulated by Pellinos and initiates signaling by most TLRs involved in SLE, we hypothesize that IRAK4 and
Pellino-1/3 play a critical role in lupus and that inhibition of IRAK4 activity will block SLE-promoting
pathways. The hypothesis will be tested in the following Specific Aims: 1. Define the role of IRAK4
expression and activity in lupus development; 2. Identify the impact of Pellino-1 and Pellino-3 on murine lupus;
and 3. Determine the ability of IRAK4 peptide inhibitors to block murine lupus. We expect to reveal how altered
IRAK4 expression and activity underlies SLE, to mechanistically define the role of IRAK4 and TLR regulators
Pellino-1 and Pellino-3 in lupus, and determine the utility of IRAK4 peptide antagonists for inhibiting murine
lupus. These findings will advance our understanding of IRAK4 signaling in SLE, facilitate design of drugs to
attenuate lupus development, and pave the way for translational studies in SLE patients. Such advances would
be of key importance for basic immunology of SLE, and for improving public health of lupus patients in the U.S.

## Key facts

- **NIH application ID:** 9920669
- **Project number:** 5R01AI136955-03
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Anthony T Vella
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $398,750
- **Award type:** 5
- **Project period:** 2018-06-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920669

## Citation

> US National Institutes of Health, RePORTER application 9920669, IRAK4 and Systemic Lupus Erythematosus (5R01AI136955-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9920669. Licensed CC0.

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