Delayed platelet recovery, and attendant bleeding complications, is a major determinant of morbidity and mortality following myelosuppressive/myeloablatlve chemoradiotherapy. Hematopoiesis is critically dependent on the interplay of temporally expressed adhesion molecules that create relevant growth niches within the bone marrow. The stage-dependent display and function of distinct adhesion molecules is tightly controlled by hematopoietic cytokines and chemokines, which promote or inhibit hematopoietic stem cell (HSC) proliferation, differentiation, maturation and migration. These effects are mediated in part by modulation of cell surface lactosaminyl glycans, especially those containing terminal sialic acid and fucose modifications. Expression of these structures within hematopoietic marrow cells occurs in a stage-specific and lineage-specific fashion. In studies to date using mice deficient in the (pi,4)-galactosyltransferase, P4GalTl, we have obtained direct evidence that lactosaminyl glycans are key regulators of thrombopoiesis. In this project, we seek to define the distinct lactosaminyl glycans expressed on mouse and human megakaryocyte progenitors (MKPs) and megakaryocytes (MKs), and the pertinent protein scaffolds and lipids that present these glycans critical for thrombopoiesis. We will define the changes in surface lactosaminyl glycans induced by thrombopoletic chemokines and cytokines or bone marrow endothelial cells (BMECs), and examine how these lactosaminyl structures mediate adhesive interactions with BMECs critical to hematopoiesis in vitro and in vivo. To obtain knowledge translatable to practical therapeutic strategies, we will extend our studies to human cells to specifically determine how deficiency in p4GalT1 affects human thrombopoiesis and lactosaminoglycan surface expression. We will determine the pertinent protein scaffolds and lipids that present lactosaminoglycans critical for thrombopoiesis in human MKs and analyze the effects of chemokines and cytokines or BMECs on lactosaminoglycan expression. We will examine how changes in surface lactosaminoglycans on human MKs affect adhesive functions with BMECs in vitro and in vivo. These studies will address fundamental questions regarding the glycobiology of thrombopoiesis. We will also investigate the capacity of platelets to serve as mediators of extrinsic glycosylation. The generated information will serve to develop strategies to modulate expression of key terminal lactosaminyl glycans to enhance thrombopoiesis and platelet production following myelosuppressive/myeloablatlve chemoradiotherapy and in other conditions of thrombocytopenia, including bone marrow failure states.
Bleeding complications following myelosuppressive/myeloablative chemoradiotherapy due to delayed platelet recovery are a major determinant of morbility and mortality. Increasing platelet production following myelosuppressive/myeloablative chemoradiotherapy will decrease the need for platelet transfusions and associated side effects, such as sepsis and antibody refractoriness to platelet transfusion.
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