John Dedman
Title: Professor
Address:
Genome Research Institute
University of Cincinnati Medical Center
2180 E. Galbraith Road
Cincinnati, OH 45237-0521
Tel: (513) 558-4145
Email: john.dedman@uc.edu
John Dedman is a professor in the Department of Cancer and Cell
Biology. 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.