T. Kendall Harden

PhD, UNC-Chapel Hill, Molecular Therapeutics

T. Kendall Harden

UNC-Chapel Hill
Molecular Therapeutics

1140A FLOB

Area of interest

G protein-mediated signaling

The physiological responses of many hormones, neurotransmitters, growth factors, nd other extracellular stimuli are initiated by activation of a large family of eterotrimeric G protein-coupled receptors. Research in this laboratory primarily tilizes purified proteins and mammalian cells engineered to express wild-type or mutant proteins to examine molecular aspects of the regulatory proteins (G protein - and bg-subunits, RGS proteins, and phospholipase C isoenzymes) involved in hosphoinositide-dependent signaling, and to investigate mechanistic and harmacological aspects of a class of Gq/phospholipase C-coupled receptors P2Y receptors) for extracellular nucleotides. This work includes delineation of regulatory domains and sites of regulation by phosphorylation in these proteins. We recently purified several of the P2Y receptors to homogeneity and functionally reconstituted these proteins with Gq, phospholipase C-b, and various RGS proteins. Studies pursuing novel signaling activities and structure of mammalian and C. elegans RGS proteins are underway. In collaboration with John Sondek we are determining the structure of phospholipase C-b. Our work on the P2Y receptors has led us to studies of the biology of extracellular ATP and UTP, including examination of mechanistic aspects of nucleotide release and metabolism by ectoenzymes. Collaborations with Richard Boucher in the Cystic Fibrosis Center at UNC are designed to better understand the roles of P2Y receptors and nucleotides as signaling molecules in airway epithelial cells. The potential for therapeutic intervention at the P2Y receptors is high, and in collaboration with Ken Jacobson at the National Institute of Health, we are carrying out rational chemical synthesis of novel high affinity P2Y receptor subtype selective ligand. These molecules in turn have been applied to resolve the role of individual P2Y receptors in nucleotide regulated physiological responses, e.g. ADP-induced platelet aggregation.

Link to Publications on Reach NC site

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