P01HL151333

Molecular and Clinical Glycobiology of the Bone Marrow Environment - The life-long production of blood cells requires hematopoietic developmental programs guided by systemic and local signals to convey the dynamic need for these cells. How these signals are delivered within the intra-medullar niches remains poorly understood.

Extensive published and to-be-published information by the PIs of this program, collaborative and individually, clearly established the involvement of glycans in the guidance of hematopoietic progenitor cell fate, function, and especially in thrombopoiesis and platelet functionality. The overarching hypothesis is "cell-intrinsic and extrinsic glycan-mediated mechanisms regulate maintenance, differentiation, and function of hematopoietic cells."

Project 1 will investigate the roles of the galactosyltransferase SS4GALT1, SS1 integrin, and glycosaminoglycans (GAGs)/heparan sulfate proteoglycans (HSPGs) in thrombopoiesis at steady-state and following myeloablative stress using novel combined shared "omics" and standard approaches with Project 3. A previously unknown role of SS4GALT1 to regulate megakaryocyte (MK) expression of HSPGs will also be investigated. A functionally defined MK-biased hematopoietic stem cell will be investigated together with Project 2, especially with respect to the heavily A2,6-sialylated cell surface despite the absence of ST6GAL1 expression necessary to generate this structure.

Project 2 will investigate the role of extracellular glycosylation, especially that mediated by extrinsic ST6GAL1 using the combined "omics" approach (Project 1), how extrinsic sialylation in the hematopoietic niche is regulated, identifying the cell surface targets of sialylation; and with Project 3, understanding how the newly discovered GAG cofactor modulates extrinsic ST6GAL1 activity. Clinical myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) and preclinical mouse models will be used in a first-time assessment into the glycobiology of these marrow diseases of highly heterogeneous presentations but with the commonality of dysplastic MKs and altered platelet numbers and function, and analysis of these clinical diseases is shared across all three projects.

Project 3 will investigate the structure-function relationships of GAGs with proteins within the marrow microenvironment, such as growth factors and their receptors, and glycosyltransferases. Their roles in promoting thrombopoiesis and cell fate decisions will be interrogated using a multi-dimensional approach to identifying distinct GAG sequences. Project 3 will discover synthetic GAG mimetics as modulators of hematopoiesis/thrombopoiesis for therapeutic use.

Core A will oversee the administration of the program, Core B will provide generation and sequencing of cDNA libraries derived from bulk RNA samples and single cells, and Core C will perform comparative structural analysis of GAGs, proteomics and protein-GAG interactions, and quantitative proteomics of protein expression. The three projects are intimately intertwined and will use all cores. This program will uncover novel information to increase platelet production and help understand clinical conditions characterized by MK abnormalities.

Versiti Wisconsin

THE DIVISION OF BLOOD DISEASES AND RESOURCES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE PATHOPHYSIOLOGY, DIAGNOSIS, TREATMENT, AND PREVENTION OF NON-MALIGNANT BLOOD DISEASES, INCLUDING ANEMIAS, SICKLE CELL DISEASE, THALASSEMIA, LEUKOCYTE BIOLOGY, PRE-MALIGNANT PROCESSES SUCH AS MYELODYSPLASIA AND MYELOPROLIFERATIVE DISORDERS, HEMOPHILIA AND OTHER ABNORMALITIES OF HEMOSTASIS AND THROMBOSIS, AND IMMUNE DYSFUNCTION. FUNDING ENCOMPASSES A BROAD SPECTRUM OF HEMATOLOGIC INQUIRY, RANGING FROM STEM CELL BIOLOGY TO MEDICAL MANAGEMENT OF BLOOD DISEASES AND TO ASSURING THE ADEQUACY AND SAFETY OF THE NATION'S BLOOD SUPPLY. PROGRAMS ALSO SUPPORT THE DEVELOPMENT OF NOVEL CELL-BASED THERAPIES TO BRING THE EXPERTISE OF TRANSFUSION MEDICINE AND STEM CELL TECHNOLOGY TO THE REPAIR AND REGENERATION OF HUMAN TISSUES AND ORGANS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Milwaukee, Wisconsin 53226 United States

Single Zip Code

NHLBI Program Project Applications (P01 - Clinical Trials Optional) (PAR-18-405)

Amendment Since initial award the total obligations have increased 391% from $2,504,440 to $12,294,902.