# Inflammatory Caspase Activation in Sickle Cell Disease

> **NIH NIH F30** · BAYLOR COLLEGE OF MEDICINE · 2024 · $49,362

## Abstract

PROJECT SUMMARY/ABSTRACT
Sickle cell disease (SCD) is an inherited red blood cell disorder that impacts millions of people worldwide.
Patients with SCD undergo chronic hemolysis which results in the release of large amounts of free heme, the
small molecule co-factor of hemoglobin. Free heme levels are elevated in SCD patients and free heme
activates many pro-inflammatory pathways. Heme-induced inflammation contributes to the major
complications of SCD including acute vaso-occlusion (painful blockages of blood vessels), acute chest
syndrome (life-threatening acute lung injury), and chronic pain. Many patients develop these serious
complications even while taking existing standard of care therapies. Thus, it is critical to characterize the
inflammatory mechanisms that underlie these complications to hasten the development of effective targeted
therapies.
Our lab identified a key pro-inflammatory protein activated by heme, caspase-4. Once activated, caspase-4
induces IL-1β release and pyroptosis, a form of inflammatory cell death, in macrophages. Circulating IL-1β
levels are elevated in patients with SCD and macrophages from patients with SCD release significantly more
IL-1β after heme exposure indicating this pathway is upregulated and active in patients. However, it remains
unknown how heme activates caspase-4 and how caspase-4 activation contributes to inflammatory
complications of SCD.
To fill this gap in knowledge and explore the suitability of caspase-4 as a druggable target in SCD, this project
will address the following two aims: 1) determine how heme activates caspase-4 through binding interaction
studies and mutagenesis and 2) determine the impact of heme-induced caspase-4 activation on inflammatory
complications of SCD in a SCD mouse model. The long-term goal of this project is to develop therapeutics to
inhibit this pathway and prevent inflammatory complications in patients. The collaborative training environment
at Baylor College of Medicine and Texas Children’s Hospital, the cutting-edge core facilities at these
institutions, and the many experts in hematology and innate immunity in the Texas Medical Center will
strongly support the success of this project. Overall, this project will comprehensively prepare the applicant for
a future career as a hematologist-scientist while providing important insights into the underlying
pathophysiology of sickle cell disease.

## Key facts

- **NIH application ID:** 10996446
- **Project number:** 1F30HL172590-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Suruchi Salgar
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $49,362
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996446

## Citation

> US National Institutes of Health, RePORTER application 10996446, Inflammatory Caspase Activation in Sickle Cell Disease (1F30HL172590-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10996446. Licensed CC0.

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