[R00] Synthetic glycosaminoglycan mimetics as regulators of megakaryopoiesis and thrombopoiesis
Ente: National Heart Lung and Blood Institute
Scadenza: 2027-06-30
Importo max: 223.435 EUR
Paese: US
Descrizione
Platelet production occurs through megakaryopoiesis, where hematopoietic stem cells differentiate into
mature megakaryocytes (MKs), and thrombopoiesis, where platelets are released into the bloodstream via
MK extensions. Platelet homeostasis is crucial for preventing thrombosis and relies on a delicate balance
between platelet production and clearance. Thrombocytopenia, low platelet count, arises from impaired
platelet production, increased platelet clearance, and platelet sequestration and results in increased risk of
hemorrhages. Therapeutic options for this condition are limited due to inadequate understanding of the
mechanisms and molecular regulators of megakaryopoiesis and thrombopoiesis. For instance, the roles
and molecular targets of cell surface and extracellular matrix glycosaminoglycans (GAGs) in these
processes are not well characterized. Recently, the GAG, heparan sulfate (HS) has been identified as the
physiological ligand of G6b-B a megakaryocyte and platelet receptor, critical for megakaryopoiesis and
thrombopoiesis, but the heterogeneous nature of GAGs and the challenges associated with obtaining them
in homogeneous forms remain bottlenecks for elucidating the relevance of the HS–G6b-B interaction. To
probe the HS–G6b-B interaction and to advance a novel potential therapeutic strategy for
thrombocytopenia, we are utilizing non-saccharide GAG mimetics (NSGMs). NSGMs are fully synthetic
homogenous sulfated compounds which feature an aromatic scaffold in place of the GAG sugar backbone,
and mimic GAG structure and function. Notably, NSGMs are more accessible in pure forms and ample
quantities and have been shown to have superior biological activity compared to their parent GAG
molecules in some instances. We have identified G4.2, a flavonoid-based NSGM that enhances
megakaryopoiesis and thrombopoiesis in vitro and in vivo. Our preliminary studies show that G4.2 binds
with high affinity to G6b-B and promotes its dimerization, a requirement for downstream signaling. Based
on our data, we hypothesize that G4.2’s enhancement of megakaryopoiesis and thrombopoiesis is in part
by its interaction with G6b-B. Our specific aims are to 1) determine the interaction of G4.2 with G6b-B at
the molecular level, 2) evaluate the selectivity of G4.2 for G6b-B and characterize its interactome, and 3)
generate a chemical library of G4.2 analogs and elucidate structure-function-relationships. These studies
will allow us to understand the mechanism(s) of action of G4.2, validate G6b-B as a drug target for
thrombocytopenia, and identify other potential therapeutic targets for thrombocytopenia. For our work, we
have developed novel tools including photoaffinity labeling-based approaches for target identification and
structural biology, which can be broadly applied to studies of GAG-protein interactions and thus significantly
advance GAG research.
Istituzione: UNIVERSITY OF NORTH TEXAS
PI: Daniel Kwame Afosah
Progetto: 5R00HL161423-05
Settori: National Heart Lung and Blood Institute
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