Like neurons, the cardiac myocyte appears to be especially susceptible to protein aggregation with aging and during disease states such as heart failure. The unfolded protein response and endoplasmic reticulum (ER) stress pathways appear to be uniquely regulated in the heart, possibly because of how this celltype has to deal with production of large sarcomeric proteins and the production and continual remodeling of an elaborate extracellular matrix (ECM), with synthesis of many large extracellular proteins. In the past funding cycle of this award we identified thrombospondins, which comprise a family of 5 genes (Thbs1-5) and are calcium binding matracellular proteins, as critical regulators of the ER stress response in the heart. Here we propose the hypothesis that thrombospondin proteins are intracellular regulators of an adaptive ER stress response that protects the heart from injury or protein aggregation-based disease. We further hypothesize that thrombospondin3/4 genes are exclusively cardioprotective while thrombospondin1/2 have both adaptive and maladaptive functional domains. To address these hypotheses we propose 2 specific aims.
Aim #1 will examine the function of all 5 thrombospondin genes in the heart, both by transgenesis to overexpress each, as well as in gene-targeted mice in which multiple family members are deleted.
Aim #2 will examine the intracellular mechanisms whereby thrombospondin proteins provide protection as either due to ATF6a activity or a more general chaperone activity associated with large ECM proteins and other secreted proteins. The overall paradigm that these aims should help establish; that being a critical or primordial function for thrombospondins as intra-vesicular regulators in the ER compartment and Golgi, would be completely novel and hence innovative. The results would also suggest new molecular targets for exploitation in treating select forms of heart disease.

Public Health Relevance

The ER stress response appears to be a universal feature of all cardiomyopathies. However, there are very few data directly examining if the ER stress response is beneficial or detrimental to the heart. We have identified novel regulators of the ER stress response, the thrombospondin proteins, which appears to only engage the protective ER stress response. Understanding how and why thrombospondins have this role is of great medical relevance.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Adhikari, Bishow B
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Cincinnati Children's Hospital Medical Center
United States
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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

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