It is the central hypothesis of this grant that the protein kinase, glycogen synthase kinase-3b (GSK-3b) is a negative regulator of hypertrophic growth of the heart. Over the past several years we have presented evidence to support that hypothesis. However, virtually all of the work in this area has relied upon over-expression of GSK-3b, and this can cause spurious results. This reliance on over-expression strategies has been necessitated by the embryonic lethality caused by deletion of the GSK-3b gene. Herein, we propose to definitively determine the role of this kinase and its isoform, GSK-3a, in the hypertrophic response using genetic loss of function approaches. This is now possible due to the recent creation by our long-time collaborator, Dr. James Woodgett, of mice in which either GSK-3b or GSK-3a can be conditionally deleted, selectively in the heart. Thus we propose to determine the role of GSK-3b in the hypertrophic response to three clinically relevant models: 1) banding of the aorta, mimicking aortic valve disease, 2) myocardial infarction, and 3) the """"""""two-kidney one clip"""""""" model of systemic hypertension. We will also determine what role, if any, GSK-3a plays in hypertrophic responses- an area that is, to our knowledge, totally unexplored. Finally, we will make use of a mouse we have recently created that conditionally expresses an inhibitory mutant of lymphocyte enhancer factor-1 (Lef-1), a transcription factor that is an obligate partner of b-catenin, a key downstream target of GSK-3b that we have recently found regulates the hypertrophic response. We will employ this mouse to attempt to identify novel targets of b-catenin that are expressed following pressure overload and that, therefore, might play a role in the genetic re-programming that is necessary for hypertrophy. We believe the studies outlined herein could identify novel targets, inhibition of which could retard or reverse the process of hypertrophy, a major risk factor for heart failure, stroke, and myocardial infarction.
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