• John Dedman

John Dedman's Lab
John Dedman is a professor in the Department of Molecular Oncogenesis. The primary focus of his research is to elucidate the molecular mechanisms that lead to heart disease, which is a leading cause of disability and death. There are two distinct forms; congestive heart failure and cardiac arrhythmias. Sustained hypertension, a consequence of atherosclerosis, obesity or diabetes mellitus, leads to dilated cardiomyopathy and inadequate perfusion of the lungs and kidneys. Clinical consequences include progressive congestive heart disease, physical disability and death. In contrast, cardiac arrhythmias are the uncoordinated, erratic contractions of the heart and are the greatest cause of sudden death. Contractile function of individual cardiomyocytes is directly related to Ca2+ transients which control each cardiac contraction-relaxation cycle. Ca2+-CaM dependent protein kinase II (CaMKII), regulates the contractile (systolic) and relaxation (diastolic) events and is an excellent therapeutic target for treatment of heart disease.The Dedman laboratory has developed three independent approaches to identify therapeutic inhibitors of CaMKII. The first entails molecular remodeling of KN93, an inhibitor compound currently in non-clinical use. Structural activity relationships (SAR) are characterized in order to identify related compounds in established, chemically-defined repositories, for increased sensitivity, specificity and nontoxicity. CaMKII recognizes three classes of consensus phosphorylation motifs that are distinct from other kinases. These motifs may reflect a CaMKII isoform or splice variant preference that may be identified by a substrate-based peptide approach. The third approach utilizes the Evotec plate:explorer system for automated high-throughput screening of the UC GRI repository of over 250,000 unique chemical structures for inhibitors of intracellular Ca2+-activated CaMKII autophosphorylation.

Selected Publications:
(none)