Biomedical stress pathways and cardiomyopathy

University Of California San Diego, La Jolla CA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The interaction between biomechanical stimuli, such as pressure and volume overload, with discrete hypertrophy, survival, and cell death pathways, plays an important role in the initiation of cardiomyopathy and heart failure. Project 1, ?Biomechanical Stress Pathways and Cardiomyopathy? (K.R. Chien), focuses on molecular pathways that mediate biomechanical stress-induced cardiac responses, based on new genetic pathways for cardiac hypertrophy and cardiomyopathy. The project utilizes unique genetically engineered animal models and novel physiological technology to dissect complex phenotypes in living animals, cardiac papillary muscle preparations, and single cardiac myocytes. Continuing our longstanding interest in pg130 pathways for cardiac hypertrophy and myocyte survival, we have recently identified a downstream component (SOCS3) in the gp130 pathway as being rapidly and markedly induced following in vivo pressure overload. SOCS3 is part of a stress-inducible negative feedback loop that prevents the hyper-stimulation of the gp130 pathway. These studies will examine the role of SOCS3 inhibition as a new therapeutic strategy to promote myocyte survival and to prevent the onset of diverse forms of cardiomyopathy. In continuation of our previous studies on the role of mutations in the Z disc protein MLP in dilated cardiomyopathy, we have recently identified MLP as part of the endogenous titin-telethonin complex. This MLP-telethonin interaction is critical for the maintenance of the stretch induced hypertrophy response. We have recently uncovered a mutation in MLP that is associated with human dilated cardiomyopathy in patients with idiopathic forms of the disease. The point mutation results in a severe charge change in a highly conserved residue in the telethonin interacting domain of MLP located in the aminoterminus and interrupts the ability of MLP to interact with telethonin, a known genetic cause of human cardiomyopathy. Similarly, we have identified patients with a deletion in the MLP interacting domain of telethonin. Accordingly, the specific aims are: 1) to identify the effects of the SOCS3 negative feedback loop on cardiac hypertrophy, myocyte survival, and cardiomyopathy in multiple model systems via studies of cardiac restricted SOCS3 KO mice; 2) to directly examine the effects of human mutations in MLP on biomechanical stretch responses and specific features of dilated cardiomyopathy; and 3) to examine the effects of mutations in specific domains of telethonin and telethonin phosphorylation on MLP binding, stretch activation responses, and dilated cardiomyopathy in genetically engineered mouse model systems.