This R01 application will investigate a novel signaling pathway, the Hippo pathway, in mammalian heart regeneration. The long-term goal is to develop new treatments for patients with heart failure by generating new cardiomyocytes in the adult heart. The objectives of this application are to gain insight into molecular properties of cardiac tissue that are regulated by Hippo signaling. The central hypothesis is that Hippo signaling is a negative regulatory pathway that prevents cardiomyocyte regeneration in the adult mammalian heart.
The specific aims are to determine whether the Hippo and Wnt pathways regulate adult heart regeneration in a manner similar to the interaction in heart development; to determine whether the sumoylation post-translation modification is an important mechanism in Yap regulation; and to determine whether Hippo functions in the context of a chronic scar after myocardial infarction. The project is conceptually and technically innovative. Concepts to be tested include new ideas in cardiomyocyte biology and cutting edge genome editing technologies to address hypotheses. The significance is high because there are no treatments for heart failure due to cardiomyocyte loss. Devising ways to generate new cardiomyocytes is highly significant.

Public Health Relevance

Heart failure due to cardiomyocyte (heart cell) loss and pump dysfunction after ischemic heart disease is the leading cause of death in the United States. We strive to facilitate cardiac regeneration after heart damage to improve survival rates. The limited ability of adult heart cells (cardiomyocytes) to divide and multiply negatively impacts the capacity of the heart to repair itself after acute damage. Our goal is to devise new methods to promote heart repair.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schwartz, Lisa
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Texas Heart Institute
United States
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Scavuzzo, Marissa A; Hill, Matthew C; Chmielowiec, Jolanta et al. (2018) Endocrine lineage biases arise in temporally distinct endocrine progenitors during pancreatic morphogenesis. Nat Commun 9:3356
Xiao, Yang; Hill, Matthew C; Zhang, Min et al. (2018) Hippo Signaling Plays an Essential Role in Cell State Transitions during Cardiac Fibroblast Development. Dev Cell 45:153-169.e6
Li, Lele; Tao, Ge; Hill, Matthew C et al. (2018) Pitx2 maintains mitochondrial function during regeneration to prevent myocardial fat deposition. Development 145:
Wang, J; Martin, J F (2017) Hippo Pathway: An Emerging Regulator of Craniofacial and Dental Development. J Dent Res 96:1229-1237
van Vliet, Patrick P; Lin, Lizhu; Boogerd, Cornelis J et al. (2017) Tissue specific requirements for WNT11 in developing outflow tract and dorsal mesenchymal protrusion. Dev Biol 429:249-259
Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas et al. (2017) Cardiomyocyte Regeneration: A Consensus Statement. Circulation 136:680-686
Martin, James F; Perin, Emerson C; Willerson, James T (2017) Direct Stimulation of Cardiogenesis: A New Paradigm for Treating Heart Disease. Circ Res 121:13-15
Jarrett, Kelsey E; Lee, Ciaran M; Yeh, Yi-Hsien et al. (2017) Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease. Sci Rep 7:44624
Leach, John P; Heallen, Todd; Zhang, Min et al. (2017) Hippo pathway deficiency reverses systolic heart failure after infarction. Nature 550:260-264
Morikawa, Yuka; Heallen, Todd; Leach, John et al. (2017) Dystrophin-glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation. Nature 547:227-231

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