A Novel Regulator of Erythrocyte Hydration and Red Blood Cell Traits

About This Grant

Project Description/Summary Reticulocyte maturation, the final stage of erythropoiesis, is critical for blood formation. Despite its importance in disease pathology, including inherited and acquired disorders of the erythrocyte, it is an understudied area. A major aspect of reticulocyte maturation is gradual loss of salt and water over time. Maintenance of water and solute homeostasis is critical to survival of both the reticulocyte and the mature erythrocyte. We have identified a novel regulator of erythrocyte hydration in erythropoiesis. In conjunction with the kinase WNK1, this TGF beta- stimulated clone (TSC) 22 family member controls potassium-chloride cotransport in reticulocytes and mature erythrocytes, shrinking reticulocytes to their normal volume in mature red blood cells. The goal of specific aim one is the identification of interacting proteins and characterization of regulator-WNK1 interactions and their influence on cellular hydration. The goal of specific aim two is elucidation of the influence of genetic variants on erythrocyte phenotype in humans and murine in vivo models of perturbed erythrocyte hydration. The overall goal of this proposal, which combines state of the art cellular, molecular, and genetic technologies in an innovative, multidisciplinary manner, is to characterize the structure and function of regulatory complexes in erythroid cells to better understand the mechanisms regulating erythrocyte volume homeostasis. These studies will extend our knowledge of normal erythropoiesis, particularly reticulocyte maturation. They will also provide a better understanding of the contribution of regulatory proteins to erythroid cell traits and its contribution to erythroid cell phenotype in inherited and acquired disorders of the erythrocyte.