Heart disease remains the most common cause of death in our society. While therapies have evolved considerably over the past decades, this evolution has paralleled the creation of a growing number of patients with chronic heart failure. Our broader understanding of the pathophysiology of disease beyond the renin- angiotensin-aldosterone system is necessary to develop additional tools to treat heart failure. The role of the ubiquitin proteasome system (UPS) and autophagy in maintaining critical protein quality control functions in the heart has gained increasing attention due to the apparent role of misfolded proteins in the pathogenesis of heart failure. However, there is a broad gap in our understanding of how the UPS and autophagy systems are directed by ubiquitin ligases, the proteins that give specificity to both systems. The broad long-term goal of this project is to delineate the mechanisms that Muscle Ring Finger (MuRF) ubiquitin ligases regulate PPAR?, PPAR/?, and PPAR?1 activities, mitochondrial dynamics, and autophagy in the context of heart failure. Based on our preliminary studies, our central hypothesis is that the MuRF ubiquitin ligases are regulate PPAR?, PPAR/?, and PPAR?1 activities, control mitochondrial ROS, and are involved in autophagy to contextually protect cardiomyocytes in heart failure. A corollary hypothesis is that inhibiting MuRF1 may specifically protect against Calpain1-induced heart failure to provide a more specific cardioprotective anti-Calpain1 target in vivo. Our hypothesis predicts that inhibiting specific MuRF activities may be detrimental in heart failure where PPAR signaling is central to its pathogenesis (diabetic cardiomyopathy) or helpful where Calpain1 is mediates heart failure (ischemia reperfusion injury). The central hypothesis will be tested by completing the following Specific Aims (SA): (1) Elucidate the unique roles of MuRF family ubiquitin ligases in diabetic cardiomyopathy and heart failure. (2) Determine the molecular mechanisms MuRF1-dependent Calpain1 activity regulates cardiac mitochondrial function and ROS. (3) Determine the mechanisms cardiac MuRF1 regulates autophagy in vivo to enhance the heart's resistance to ischemia reperfusion injury and heart failure. For SA1, we will characterize the mechanisms MuRF2 and MuRF3 are protective in a high fat diet induced diabetic cardiomyopathy. For SA2, we'll determine the role of MuRF1-dependent Calpain1 in regulating ROS, mitochondrial dynamics, and eEF2 in heart failure. SA3 investigates the mechanisms MuRF1 regulates autophagy to integrate additional ways in which inhibiting MuRF1 may be contextually protective in heart failure. The present studies offer innovative paradigms elucidating the mechanisms in which MuRF proteins may be targeted for their ability to protect the heart in the context of heart failure.

Public Health Relevance

The proposed research is relevant to public health as understanding novel mechanisms regulating cardiomyocyte signaling through muscle-specific MuRF ubiquitin ligases will further our understanding new ways to targeting heart failure therapies. By delineating specific activities MuRF proteins regulate the adaptive responses in heart failure, including metabolic remodeling, mitochondria protein quality control, and autophagy; we can test their utility as druggable targets. The proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help reduce and treat cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL104129-07S1
Application #
9276196
Study Section
Program Officer
Adhikari, Bishow B
Project Start
2016-09-01
Project End
2019-05-31
Budget Start
2016-09-01
Budget End
2017-05-31
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Willis, Monte S; Holley, Darcy Wood; Wang, Zhongjing et al. (2017) BRG1 and BRM function antagonistically with c-MYC in adult cardiomyocytes to regulate conduction and contractility. J Mol Cell Cardiol 105:99-109
Starnes, Joseph W; Parry, Traci L; O'Neal, Sara K et al. (2017) Exercise-Induced Alterations in Skeletal Muscle, Heart, Liver, and Serum Metabolome Identified by Non-Targeted Metabolomics Analysis. Metabolites 7:
Mota, Roberto; Rodríguez, Jessica E; Bonetto, Andrea et al. (2017) Post-translationally modified muscle-specific ubiquitin ligases as circulating biomarkers in experimental cancer cachexia. Am J Cancer Res 7:1948-1958

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