REGULATION OF SICKLE CELL PHOSPHOLIPID ORGANIZATION

Children'S Hospital &Res Ctr At Oakland, Oakland CA

Investigators

Linked publications & trials

Abstract

The presence of phosphatidylserine (PS) exposing red cells is linked to the pathophysiology of sickle cell disease (SCD), including imbalance in hemostasis, risk for stroke, increased red cell endothelial interaction and vascular damage. Our long term goal is to understand the mechanisms that lead to the loss of phospholipid asymmetry and the exposure of PS in red cell membranes, why these cells are present at such a high level in SCD, and how they result in SCD pathology. We hypothesize a novel chain of events in which (inflammatory) lipid mediators trigger signal transduction pathways leading to PS exposure on the red cell surface. In addition, these lipid mediators may influence cell-cell interaction. To address the dynamic mechanisms that will lead to PS exposure and affect red cell endothelial interaction, we have developed the following specific aims: I. To assess the influence of the increased presence of inflammatory lipid mediators in SCD on the loss of phospholipid asymmetry in subpopulations of sickle ceils. II. To investigate the role of intracellular signaling pathways in the erythrocyte in the regulation of the flipase and the scramblase., and III. To investigate the role of altered erythrocyte lipids on cell-cell interaction and physiological processes in the circulation. To accomplish these goals, we will use a multidisciplinary approach using biochemistry and cell biology techniques to study red cells and endothelial cells under well-defined conditions. We will use blood samples from SCD patients as well as a transgenic mouse model for SCD. We will measure the presence of lipid mediators such as LPA in vivo, measure the generation of LPA in vitro and define its role. We will relate the data of in vitro studies to in vivo findings in SCD patients with vaso-occlusive crisis, stroke and acute chest syndrome, as well as in our murine model for SCD. Together, our results may indicate novel treatment regimens in the management of SCD.