The long term objectives of this proposal are (1) to understand the genetic regulation sarcoplasmic reticulum (SR) Ca2+ ATPase ene expression and 2 to define the role of altered SR Ca2+ ATPase expression in normal cardiac performance and congestive heart failure. The SR Ca2+ ATPase plays a central role in excitation contraction coupling of cardiac muscle. It is primarily responsible for the active transport of calcium into the SR vesicle. This lowers cytosolic calcium levels, thus permitting muscle relaxation. Recent findings suggest that the SR Ca2+ ATPase mRNA/protein levels and Ca2+ uptake function are substantially reduced in a coordinate fashion both in animal models of cardiac hypertrophy and in end stage human heart failure. Despite the obvious importance of SR Ca2+ ATPase in cardiac muscle physiology and possibly pathophysiology, relatively little is known of the mechanisms that regulate its' expression. There is data to suggest that SR Ca2+ ATPase is controlled at the level of transcription. Therefore, a primary goal of this proposal is to dissect the cis and trans-regulatory mechanisms controlling SR Ca2+ ATPase gene expression during normal and pathological states of the heart, as we hypothesize that the myocardial dysfunction in congestive heart failure is a partial consequence of altered Ca2+ ATPase expression. A second major goal of this proposal is to test this hypothesis directly in the whole animal by perturbing SR Ca2+ ATPase expression levels. To achieve these objectives, the following specific aims will be pursued: 1) Delineate cis-DNA control elements involved in transcriptional regulation of the SR Ca2+ ATPase gene in cardiac and skeletal muscle cells; 2) Identify nuclear protein factors that interact specifically with the SERCA2 promoter and modulate gene expression; 3) Delineate cis-DNA control elements responsible for tissue specific and pathophysiological regulation of the SR Ca2+ ATPase gene under in vivo conditions; 4) Create a transgenic animal model with alterations in SR Ca2+ transport function; and 5) Determine alterations in SR Ca2+ transport protein expression in early and late human congestive heart failure, and to relate these changes to hemodynamic indices of cardiac function.
Showing the most recent 10 out of 193 publications
