A role for extra-medullar, extrinsically produced ST6Gal-1 in hematopoiesis and inflammation
Jones, Mark B.
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The sialyltransferase ST6Gal-1 is ubiquitously expressed in most cells and tissues, but it is expressed with particular abundance in the liver where the P1 promoter, one of six known distinct promoter-regulatory regions associated with ST6Gal-1, principally mediates transcription of the ST6Gal-1 gene. Hyperactive myelopoiesis coupled with greater eosinophilic and neutrophilic inflammatory responses is associated specifically with the disruption of the P1 promoter. As P1 is utilized in the liver but silent in hematopoietic lineages, we hypothesize that hematopoietic homeostasis is modulated by ST6Gal-1 of extramedullary origins, putatively from the liver. Hepatic ST6Gal-1 is used to sialylate circulatory glycoproteins of liver origin; it is also released directly into circulation. This liver-produced ST6Gal-1 is the principle source of the pool of ST6Gal-1 in the blood. This dissertation seeks to establish the link between liver expression of ST6Gal-1 and hematopoietic regulation in the bone marrow. The specific goals are: (1) to determine the contribution of circulatory hepatic glycoproteins in hematopoietic regulation; (2) to confirm the biological relevance of the systemic pool of ST6Gal-1 using transgenic models; (3) to determine if circulatory ST6Gal-1 affects additional aspects of the inflammatory response. The immediate goal of this research is to demonstrate that bone marrow hematopoietic homeostasis, and other potential compartments, are influenced by distally expressed ST6Gal-1, establishing a novel glycosylation paradigm.