The structure of the human erythrocyte membrane is described in virtually every modern Cell Biology and Hematology text, because: i) it constitutes a useful model of other plasma membranes, ii) its protein components (or homologues) are present in nearly every cell of the body, iii) its architecture is simple and well characterized, ad iv) defects or alterations in its components lead to important human diseases. The Low lab has focused for 35 years on determining the detailed structure of the red blood cell (RBC) membrane and the impact of defects in its structure on RBC properties. During the course of these studies, the lab has been able to demonstrate that most protein interactions in the membrane are regulated and have significant consequences on RBC properties. However, because the biology of RBC signal transduction has received little attention to date, and since dysfunctions in these signaling pathways can lead to serious human diseases, the goals of this proposal are to characterize two of the most important RBC signaling pathways (i.e. those mediated by O2 and tyrosine phosphorylation) and determine the mechanism by which defects in these pathways contribute to human pathologies.
In Aim 1 transgenic mice will be used to examine whether the oxygen dependent interaction of hemoglobin with band 3 constitutes the """"""""molecular switch"""""""" by which oxygen regulates many critical RBC properties.
In Aim 2, the mechanisms by which tyrosine phosphorylation of band 3 induce RBC membrane destabilization and vesiculation will be explored by evaluating protein interactions associated with a unique SH2 domain in band 3.
In Aim 3, a potent inhibitor of this latter pathway will be examined for its impact on the maturation of Plasmodium falciparum within infected red cells and thereby tested as a possible treatment for malaria.
The studies proposed here will investigate the mechanisms by which oxygen pressure and tyrosine phosphorylation regulate red blood cell membrane properties, including membrane stability, membrane vesiculation, cell volume, glucose metabolism, and release of vasodilating agents. Because malfunction of any of these signaling pathways can have serious health consequences, information on the pathways may guide development of new therapies for important human diseases.
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