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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL107146-04
Application #
8669077
Study Section
Special Emphasis Panel (ZHL1-CSR-H (F1))
Program Officer
Sarkar, Rita
Project Start
2011-07-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$2,438,864
Indirect Cost
$673,171
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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