Heart disease caused by the loss or dysfunction of cardiomyocytes is the leading cause of death worldwide. The adult mammalian heart possesses little regenerative potential and therefore displays fatal loss of function following myocardial infarction (MI) and other heart diseases. Fibrosis and scar formation due to activation of cardiac fibroblasts serve as barriers to cardiac regeneration and contribute to loss of contractile function, pathological remodeling and susceptibility to arrhythmias. Recently, combinations of cardiogenic transcription factors were shown to be capable of activating cardiac gene expression in fibroblasts in vitro. Moreover, we have shown that forced expression of four transcription factors in cardiac fibroblasts is sufficient to activate cardiac gene expression in vivo, leading to improvement of cardiac function and reduction of adverse ventricular remodeling following MI in mice. Although these reprogramming processes are not yet optimized, they hold great potential for eventual cardiac repair, avoiding many of the obstacles associated with cellular transplantation. The overall goals of this project are to further define the mechanisms involved in reprogramming of cardiac cell fate and to optimize the technology for reprogramming of fibroblasts to cardiomyocytes in vivo as a strategy for cardiac repair. We will also assess the ability of selected small molecules and microRNAs to enhance cardiac reprogramming in vivo as a strategy for restoration of cardiac function following MI. These studies will provide important new insights into the mechanisms of cardiac cell fate specification and differentiation and will pave the way toward innovative approaches for cardiac repair.
Ischemic heart disease resulting in myocardial infarction (MI) and heart failure is the leading cause of morbidity and mortality in the United States. Recent studies have suggested a new approach for restoration of cardiac function following MI, through conversion of cardiac fibroblasts into cardiomyocytes by the introduction of defined cardiac transcription factors. In this project, this approach will be optimized using combinations of cardiogenic transcription factors, small molecules and microRNAs and the cellular and molecular mechanisms underlying cardiac reprogramming in vitro and in vivo will be defined.
|Anderson, Douglas M; Cannavino, Jessica; Li, Hui et al. (2016) Severe muscle wasting and denervation in mice lacking the RNA-binding protein ZFP106. Proc Natl Acad Sci U S A 113:E4494-503|
|Nelson, Benjamin R; Makarewich, Catherine A; Anderson, Douglas M et al. (2016) A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle. Science 351:271-5|
|Long, Chengzu; Amoasii, Leonela; Mireault, Alex A et al. (2016) Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science 351:400-3|
|Karsenty, Gerard; Olson, Eric N (2016) Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication. Cell 164:1248-56|
|Polster, Alexander; Nelson, Benjamin R; Olson, Eric N et al. (2016) Stac3 has a direct role in skeletal muscle-type excitation-contraction coupling that is disrupted by a myopathy-causing mutation. Proc Natl Acad Sci U S A 113:10986-91|
|Amoasii, Leonela; Holland, William; Sanchez-Ortiz, Efrain et al. (2016) A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism. Genes Dev 30:434-46|
|Carroll, Kelli J; Makarewich, Catherine A; McAnally, John et al. (2016) A mouse model for adult cardiac-specific gene deletion with CRISPR/Cas9. Proc Natl Acad Sci U S A 113:338-43|
|Tao, Ge; Kahr, Peter C; Morikawa, Yuka et al. (2016) Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury. Nature 534:119-23|
|Cenik, Bercin K; Liu, Ning; Chen, Beibei et al. (2016) Myocardin-related transcription factors are required for skeletal muscle development. Development 143:2853-61|
|Millay, Douglas P; Gamage, Dilani G; Quinn, Malgorzata E et al. (2016) Structure-function analysis of myomaker domains required for myoblast fusion. Proc Natl Acad Sci U S A 113:2116-21|
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