Infection secondary to neutropenia is a major cause of near-term morbidity and mortality in hematopoietic stem cell transplantation (HSCT) and in cancer therapeutics using myelosuppressive regimens. In each case, the recovery of hematopoiesis, heralded by return of granulocyte production. Is critically dependent on the combinatorial and temporal expression of adhesion molecules that create relevant myelopoietic growth niches within the marrow. Cell surface lactosaminyl glycans, particulariy those bearing terminal sialic acid and fucose modifications, serve as principal effectors, as well as modulators, of a variety of adhesive interactions essential to hematopoiesis. Conspicuously, the expression of these structures within hematopoietic cells of marrow varies distinctly in a stage-specific and lineage-specific manner. We hypothesize that changes In cell surface terminal lactosaminyl glycans help to specify the lineage fate of eariy hematopoietic progenitors, and, commensurately, proliferation and differentiation of these cells. In this project, we seek to define the terminal lactosaminyl glycans expressed on human cells among primitive progenitors, and eariy myeloid and non-myeloid progenitor subsets, obtained from sources relevant to hematopoietic stem cell transplantation (i.e., marrow, G-CSF-mobilized blood, cord blood), and the pertinent protein and/or lipid scaffolds that present these glycans. We will analyze the function(s) of terminal lactosaminyl glycans in licensing adhesive interactions critical to sustaining primitive hematopoietic cells and to driving eariy myelopoietic commitment, and, using a variety of biochemical techniques to remodel their expression, will directly examine how these structures affect hematopoietic processes, particularly myelopoietic proliferation and differentiation. We will also analyze how terminal lactosaminyl glycans mediate supportive interactions between hematopoietic stem cells and marrow stromal cells ("mesenchymal stem cells", MSCs). These studies will address fundamental Issues regarding the glycobiology of hematopoiesis in humans. It is anticipated that the information obtained will yield transformative strategies to custom-modify expression of key terminal lactosaminyl glycans to achieve the overarching clinical goals of enhancing myelopoietic recovery following myelosuppressive/myeloablatlve chemoradiotherapy, of stimulating hematopoiesis in conditions of marrow failure, and of halting dysregulated myeloproliferation such as in leukemia.
Low levels of white blood cells can result In life-threatening infections. Deficiency of white blood cells is a common complication of cancer therapy and can also occur with bone marrow diseases. Information obtained from this research effort will provide important information on how white blood cells are made, and should pave the way for new treatments to increase white blood cell production when needed.
|Liu, Zhi-Jian; Hoffmeister, Karin M; Hu, Zhongbo et al. (2014) Expansion of the neonatal platelet mass is achieved via an extension of platelet lifespan. Blood 123:3381-9|
|Liu, Gang; Neelamegham, Sriram (2014) A computational framework for the automated construction of glycosylation reaction networks. PLoS One 9:e100939|
|Nasirikenari, Mehrab; Veillon, Lucas; Collins, Christine C et al. (2014) Remodeling of marrow hematopoietic stem and progenitor cells by non-self ST6Gal-1 sialyltransferase. J Biol Chem 289:7178-89|
|Dauber, Andrew; Ercan, Altan; Lee, Jack et al. (2014) Congenital disorder of fucosylation type 2c (LADII) presenting with short stature and developmental delay with minimal adhesion defect. Hum Mol Genet 23:2880-7|
|Lee, Melissa M; Nasirikenari, Mehrab; Manhardt, Charles T et al. (2014) Platelets support extracellular sialylation by supplying the sugar donor substrate. J Biol Chem 289:8742-8|
|Ashline, David J; Hanneman, Andrew J S; Zhang, Hailong et al. (2014) Structural documentation of glycan epitopes: sequential mass spectrometry and spectral matching. J Am Soc Mass Spectrom 25:444-53|
|Batal, Ibrahim; Azzi, Jamil; Mounayar, Marwan et al. (2014) The mechanisms of up-regulation of dendritic cell activity by oxidative stress. J Leukoc Biol 96:283-93|
|Silvescu, Cristina I; Sackstein, Robert (2014) G-CSF induces membrane expression of a myeloperoxidase glycovariant that operates as an E-selectin ligand on human myeloid cells. Proc Natl Acad Sci U S A 111:10696-701|
|Dykstra, Brad; Bystrykh, Leonid V (2014) No monkeying around: clonal tracking of stem cells and progenitors in the macaque. Cell Stem Cell 14:419-20|
|Cabral, M Guadalupe; Silva, Zelia; Ligeiro, Dario et al. (2013) The phagocytic capacity and immunological potency of human dendritic cells is improved by *2,6-sialic acid deficiency. Immunology 138:235-45|
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