Monte S. Willis

Research Interests

  • Myocyte specific regulation of metabolism and the response to biomechanical force, Misfolded proteins, protein quality control, and proteotoxicity in human heart failure.

Research Synopsis 

Our laboratory investigates protein quality control in the context of heart failure. There are primary projects that emcompass this work: 1) Elucidating the role of muscle-specific ubiquitin ligases (E3s) in the regulation of metabolism and the response to biomechanical force; and 2) Determining mechanisms of proteotoxicity in heart failure and therapeutic interventions to attenuate and reverse the toxicity resulting from the accumulation of misfolded proteins.

Project 1: The broad long-term goal of this project is to delineate the mechanisms that Muscle Ring Finger (MuRF) ubiquitin ligases regulate PPARα, PPARβ/δ, and PPARγ1 activities, mitochondrial dynamics, and autophagy in the context of heart failure. Our central hypothesis is that the MuRF ubiquitin ligases are regulate PPARα, PPARβ/δ, and PPARγ1 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).

Project 2: As part of the Leducq Foundation TransAtlantic Network of Excellence, this project investigates Proteotoxicity as an unappreciated mechanism of heart disease and its potential for novel therapeutics. The network aims to define how defects in the two major pathways of protein breakdown, (the autophagy-lysosomal pathway and the ubiquitin-proteasome system), can lead to the buildup in cardiac muscle cells of unneeded or misfolded proteins and, ultimately, heart failure.  The work our laboratory has focused on involves identifying MuRF1’s regulation of autophagy and more recently identifying the causes of cardiac dysfunction resulting from human mutations in Bag3. Using a Bag3 P209L cardiac-specific mouse model, we’re investigating how pre-amyloid oligomers alter redox and MAPK signaling pathways to induce cardiac dysfunction. This work complements the overarching theme of the network investigating the proteotoxicity in genetic and non-genetic forms of heart failure to dissect out the genetic and signaling networks that regulate the two protein breakdown pathways. And similarly involves the search for targeted therapies that reduce or block proteotoxicity in the hopes of developing new clinical treatments for heart failure.


Click here for PubMed list of publications.

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