Alterations in RBC Membrane Lipids in SCD/Infection and Impact on Hemolysis

New York Blood Center, New York NY

Investigators

Linked publications, trials & patents

Abstract

Although hemolytic anemia is the most prominent manifestation of SCD, there is a wide phenotypic variability leading to a broad spectrum of disease severity. The molecular drivers of hemolysis in SCD are not fully understood, leaving a gap in the overall understanding of the disease as well as in exploring targets for therapeutics that could improve SCD pathology. Our program will characterize potential mediators of these differential clinical presentations by focusing on SCD hematological features that differ among SCD patients and identifying their cause. Our preliminary data leads us to hypothesize that intracellular ROS stemming from differential mitochondrial retention in SCD patients, among other ROS sources, causes an aberrant upregulation of key lipid desaturase enzymes that leads to an imbalance of SCD membrane phospholipids which disrupts membrane composition and organization resulting in membrane destabilization and premature hemolysis. Upon Babesia infection, the integrity of the SCD membrane is further impacted because of because of the substantial lipid requirement to support parasite proliferation and associated membrane expansion, leading to hyper hemolysis of infected SCD. Thus, we posit that some of the pathophysiology of SCD can be directly ascribed to RBC membrane properties. We will in Aim 1, Investigate the mechanisms by which altered sickle RBC membrane lipid composition leads to a hemolytic phenotype: by analyzing the defective lipid pathways and resulting membrane lipidomes in SCD RBCs and elucidating the mechanisms by which these membrane changes impact SCD RBC structure and function. Together with our AI based sickling tool, we will probe levels of cellular ROS as well as mitochondrial ROS to determine their impact on lipid modulating enzymes as well as SCD sickling rates and membrane rheology changes that lead to premature hemolysis. In Aim 2, we will Investigate the mechanisms by which Babesia infection in SCD further weakens the erythrocyte membrane by examining changes in membrane lipid composition and loss of membrane integrity via vesiculation, lipid scavenging, ion fluxes and loss of membrane asymmetry which we hypothesize causes a more severe sickling phenotype and increased fragility, resulting in hyper-hemolysis. Understanding the mechanisms that govern the maintenance of the RBC lipid bilayer and the metabolic modulation of RBC membrane remodeling in SCD, including the impact of transfusions, and defining the molecular changes in SCD membranes upon infection, may offer novel options for limiting hemolysis in this population.