Infection and bleeding secondary to neutropenia and thrombocytopenia, respectively, are the major causes of near-term morbidity and mortality from chemoradiotherapy. Hematopoietic stem/progenitor cells (HSPCs) proliferate and differentiate in specialized bone marrow microarchitectural domains known as """"""""niches"""""""" dictated by critical cell-cell and cell-matrix adhesive interactions. It is well-recognized that expression of sialyl and/or fucosyl modifications of terminal lactosaminyl glycans (i.e., at distal end of carbohydrate chains attached to protein or lipid of the cell membrane) mediate and/or modulate multiple adhesive interactions. The central hypothesis of this proposal is that these cell surface glycans critically shape formation of marrow niches that sustain HSPCs and dictate lineage fate decisions. Specifically, we wish to elucidate the role(s) of terminal lactosaminyl glycans in regulating myelopoietic and thrombopoletic processes. We seek to obtain fundamental information regarding the stage- and lineage-specific distribution of terminal lactosaminyl glycans on pertinent scaffolds of relevant progenitor cells and the biosynthetic pathway(s) that direct their expression, their structural biology (linkages and branching/multiplicity), their influence(s) on marrow adhesive interactions, and, altogether, their effect(s) on clonogenicity. This program proposal employs a multidisciplinary approach to address these central issues, offering synergistic structure-function studies integrated into three interwoven projects: Project 1 (Sackstein) will use primary human HSPCs derived from clinically-relevant sources to elucidate the temporospatial expression and function of terminal lactosaminyl glycans in early hematopoietic and myelopoietic cells, and will develop strategies to remodel surface lactosaminyl glycans;Project 2 (Lau) will investigate human and mouse HSPCs to identify the biosynthetic pathways that direct stage-specific expression of terminal lactosaminyl glycans;Project 3 (Hoffmeister) will study mouse and human megakaryocyte progenitors and megakaryocytes to define the temporal changes and function(s) of terminal lactosaminyl glycans during thrombopoiesis, and will analyze the role(s) of platelets in mediating extrinsic glycosylation pathways. Moreover, this program will establish new technical resources to interrogate glycan structure and function, and will establish a glycosciences skills development core that will provide training in the background, tools and techniques necessary for the creation of new investigators possessing the requisite knowledge and skills to drive forward the field of translational glycobiology. Thus, it is anticipated that the experiments and approaches proposed in this program will address key questions in glycobiology and in hematopoiesis enabling transformative therapeutic strategies to custom-modify surface glycans to optimize myelopoiesis and thrombopoiesis, will expand glycan analytical resources, and will also fundamentally serve to mentor/nurture the future generation(s) of scientists required to undertake investigations at the interface of glycoscience and medical necessity.
Deficiency in white cells and platelets is associated with cancer treatment, and also occurs in bone marrow diseases. This research effort should yield new treatments to improve marrow function in such conditions.
|Donnelly, Conor; Dykstra, Brad; Mondal, Nandini et al. (2018) Optimizing human Treg immunotherapy by Treg subset selection and E-selectin ligand expression. Sci Rep 8:420|
|Carrascal, Mylène A; Silva, Mariana; Ramalho, José S et al. (2018) Inhibition of fucosylation in human invasive ductal carcinoma reduces E-selectin ligand expression, cell proliferation, and ERK1/2 and p38 MAPK activation. Mol Oncol 12:579-593|
|Irons, Eric E; Lau, Joseph T Y (2018) Systemic ST6Gal-1 Is a Pro-survival Factor for Murine Transitional B Cells. Front Immunol 9:2150|
|Videira, Paula A; Silva, Mariana; Martin, Kyle C et al. (2018) Ligation of the CD44 Glycoform HCELL on Culture-Expanded Human Monocyte-Derived Dendritic Cells Programs Transendothelial Migration. J Immunol 201:1030-1043|
|Carrascal, Mylène A; Talina, Catarina; Borralho, Paula et al. (2018) Staining of E-selectin ligands on paraffin-embedded sections of tumor tissue. BMC Cancer 18:495|
|Mondal, Nandini; Dykstra, Brad; Lee, Jungmin et al. (2018) Distinct human ?(1,3)-fucosyltransferases drive Lewis-X/sialyl Lewis-X assembly in human cells. J Biol Chem 293:7300-7314|
|Silva, Mariana; Videira, Paula A; Sackstein, Robert (2017) E-Selectin Ligands in the Human Mononuclear Phagocyte System: Implications for Infection, Inflammation, and Immunotherapy. Front Immunol 8:1878|
|Manhardt, Charles T; Punch, Patrick R; Dougher, Christopher W L et al. (2017) Extrinsic sialylation is dynamically regulated by systemic triggers in vivo. J Biol Chem 292:13514-13520|
|Sackstein, Robert; Schatton, Tobias; Barthel, Steven R (2017) T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy. Lab Invest 97:669-697|
|Silva, Mariana; Fung, Ronald Kam Fai; Donnelly, Conor Brian et al. (2017) Cell-Specific Variation in E-Selectin Ligand Expression among Human Peripheral Blood Mononuclear Cells: Implications for Immunosurveillance and Pathobiology. J Immunol 198:3576-3587|
Showing the most recent 10 out of 69 publications