IDENTIFICATION OF DRUGGABLE PRO-RESOLVING MECHANISMS IN 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. New and alternative approaches are needed to reduce the burden of inflammation and cardiovascular disease in patients with SCD. The hypothesis of this project is that persistent and amplified inflammation determines SCD-related cardiovascular disease and that it is possible to treat these complications by promoting the resolution of inflammation using endogenous chemical molecules called resolvins normally produced in our body to end the inflammatory response. The broad objectives of this project are to define the role of these proresolving mechanisms in the development of cardiovascular disease in SCD and to identify new possible treatments for this pathology. To achieve this goal, we will define the link between inflammation and pro-resolving events in SCD cardiovascular disease (Aim 1), identify targets modulated by resolvins (Aim 2), and test if these targets represent treatment mechanisms for SCD-related cardiomyopathy (Aim 3). Completion of this project will advance our knowledge on mechanisms underlying 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 this new therapeutic tool will beneficially impact the progression of SCD, better preserving organ function for SCD patients candidate to either hematopoietic stem cell transplantation or gene therapy.