The ER/SR compartment in a cardiomyocyte is highly specialized for controlling calcium fluxing in excitation- contraction coupling (ECC), as well as for regulating protein synthesis and stress responsiveness to unfolded proteins. The traditional ER stress response involves sensing of calcium and unfolded or damaged proteins in the ER through 3 distinct pathways that initiate a cascade of signaling to alter protein synthesis and other features of cellular adaptation to stress. We recently identified thrombospondin 4 (TSP4) as a stress-inducible factor that resides for a period of time in the ER/SR before being secreted to the extracellular matrix (ECM), where it alters the ER stress response. The heart expresses TSP1, TSP2, and TSP4, each of which is dramatically up-regulated following injury or stress stimulation. Interestingly, TSP4 is only expressed in heart and skeletal muscle, and it appears to be of an entirely different functional subclass from TSP1 and TSP2. We have identified a novel function for TSP4 as a cardiac inducible protein that dramatically enhances the content and function of the ER/SR resulting in greater contractility, increased activity of the adaptive ER stress response, and protection from heart failure-inducing stimuli. Thus, we hypothesize that TSP4 is a novel adaptive stress-response factor that benefits ER/SR function to provide cardioprotection. In this project we will: 1) determine if TSP4 protects the heart from failure through adaptive ER stress response pathway engagement, 2) investigate the ER stress response factors that mediate TSP4-dependent cardio-protection, and 3) determine how and where TSP4 signals the adaptive ER stress response. We will use TSP4 transgenic and gene-targeted mice to investigate these 3 specific aims, as well as numerous transgenic models with altered ER stress signaling or protein aggregation-based cardiomyopathy. Extensive in vitro molecular approaches are also proposed to identify the mechanism whereby TSP4 coordinates the protective ER stress response and benefits the heart. Finally, numerous collaborations with the Kranias and Robbins lab's are proposed to determine how TSP4 affects calcium handling and the unfolded proteins response.

Public Health Relevance

The ER stress response appears to be a universal feature of all cardiomyopathies. However, there are very little data that directly examine if the ER stress response is beneficial or detrimental to the heart. We have identified a novel regulator of the ER stress response, TSP4, which appears to only engage the protective ER stress response. Understanding how and why TSP4 does this is of great medical relevance.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Adhikari, Bishow B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cincinnati Children's Hospital Medical Center
United States
Zip Code
Brody, Matthew J; Vanhoutte, Davy; Schips, Tobias G et al. (2018) Defective Flux of Thrombospondin-4 through the Secretory Pathway Impairs Cardiomyocyte Membrane Stability and Causes Cardiomyopathy. Mol Cell Biol :
Schwanekamp, Jennifer A; Lorts, Angela; Sargent, Michelle A et al. (2017) TGFBI functions similar to periostin but is uniquely dispensable during cardiac injury. PLoS One 12:e0181945
Cai, Chen-Leng; Molkentin, Jeffery D (2017) The Elusive Progenitor Cell in Cardiac Regeneration: Slip Slidin' Away. Circ Res 120:400-406
Khalil, Hadi; Kanisicak, Onur; Prasad, Vikram et al. (2017) Fibroblast-specific TGF-?-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest 127:3770-3783
Molkentin, Jeffery D; Bugg, Darrian; Ghearing, Natasha et al. (2017) Fibroblast-Specific Genetic Manipulation of p38 Mitogen-Activated Protein Kinase In Vivo Reveals Its Central Regulatory Role in Fibrosis. Circulation 136:549-561
Liu, Ruijie; van Berlo, Jop H; York, Allen J et al. (2016) DUSP8 Regulates Cardiac Ventricular Remodeling by Altering ERK1/2 Signaling. Circ Res 119:249-60
Gupta, Manish K; McLendon, Patrick M; Gulick, James et al. (2016) UBC9-Mediated Sumoylation Favorably Impacts Cardiac Function in Compromised Hearts. Circ Res 118:1894-905
James, Jeanne; Robbins, Jeffrey (2016) Healing a Heart Through Genetic Intervention. Circ Res 118:920-2
Vanhoutte, Davy; Schips, Tobias G; Kwong, Jennifer Q et al. (2016) Thrombospondin expression in myofibers stabilizes muscle membranes. Elife 5:
Brody, Matthew J; Schips, Tobias G; Vanhoutte, Davy et al. (2016) Dissection of Thrombospondin-4 Domains Involved in Intracellular Adaptive Endoplasmic Reticulum Stress-Responsive Signaling. Mol Cell Biol 36:2-12

Showing the most recent 10 out of 36 publications