Inflammatory Caspase Activation in Sickle Cell Disease

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.