A NOVEL THERAPEUTIC APPROACH TARGETING PRO-RESOLVING MECHANISMS IN THE CARDIOMYOPATHY OF SICKLE CELL DISEASE

Sickle cell disease (SCD) is an invalidating rare hereditary red cell disorder, characterized by the production of abnormal hemoglobin. People with SCD have recurrent blood flow occlusions leading to organ damages and cardiovascular complications that largely impact their life. Recently, we showed impairment of mechanism involving endogenous chemical molecules called resolvins normally produced in our body to end the inflammatory response. We demonstrate that unresolved inflammation plays a key role in the pathogenesis of sickle cell related cardiomyopathy. The broad objectives of this project are: • to select therapeutic molecule(s) targeting pro-resolving mechanisms against sickle cell cardiopathy; • to validate the more promising lead candidate for pre-clinical and clinical studies. To achieve these goals, we generated preliminary data, which allowed us to design three strictly integrated and interdependent aims. Aim 1. Integrated studies on the effects of stable specialized pro-resolving lipids in sickle cell related cardiomyopathy. Aim 2. Understanding the impact of therapeutic targeting pro-resolving mechanisms on natural history of SCD cardiomyopathy. Aim 3. Validation of the new identified therapeutic pro-resolving tools by system approaches. Completion of this project will advance our knowledge on cardiovascular disease in patients with SCD and deliver new therapeutic molecules to treat SCD that can be tested in pre-clinical and clinical studies. The development of new therapeutic tools will beneficially impact the progression of SCD, better preserving organ function for SCD patients candidate to either hematopoietic stem cell transplantation or gene therapy.