A research program targeted towards the general issue of cardiac protein degradation and the control mechanisms for the regulation thereof is presented. Emphasis is given to lysosomal protease metabolism and in particular the post translational processing of cathepsin D (CD) and cathepsin B (CB) during periods of altered cardiac protein turnover. Constant infusion techniques have been adapted to the rabbit model to permit measurement of fractional synthesis rate and degradative rate of cardiac protein in vitro in the non-steady state. Utilizing techniques previously defined in our and other laboratories we plan to specifically address the issues of: a) what is the pathway for post translational processing of CB in cardiac tissue b) is a specific isoform of CB responsible for the proteolytic post translational processing of CD? c) what is the role of the phosphomannosyl receptor in the vectorial transport of lysosomal proteases in cardiac tissue from endoplasmic reticulum to lysosomal storage sites d) what perturbations of lysosomal protease turnover and post translational processing can be identified during interventions which cause """"""""altered patterns of protein turnover"""""""" using techniques wherein the actual rates of protein synthesis and degradation have been measured during the atrophy or hypertrophy process. These studies will utilize modern techniques of protein chemistry and cell culture. Although focused upon specific issues of lysosomal protease metabolism, these studies are consistent with our overall goal of defining the mechanism(s) by which cardiac mass is regulated.
Showing the most recent 10 out of 18 publications
