Cardiac fibrosis has rapidly emerged as one of the biggest problems affecting the clinical management of heart disease to date because current treatments only delay rather than prevent fibrotic remodeling and heart failure. Fibrosis results from an unrestrained tissue repair response orchestrated predominantly by the myofibroblast. Myofibroblasts are highly specialized cells characterized by a hybrid fibroblast/smooth muscle cell phenotype, as they can contract, migrate, and secrete vast amounts of extracellular matrix. The healthy heart is normally devoid of myofibroblasts, but injury-induced alterations of the mechanical and neurohumoral environment induce fibroblasts to transform into myofibroblasts. Initially, myofibroblast function is critical to the repair process as its contractile function and matrix secretion provides structural support to the injured myocardium;however, chronic myofibroblast activity eventually causes hypertrophic scarring and cumulative fibrosis, which is not only deleterious to cardiac function but creates a highly arrhythmogenic substrate. Due to the lack of genetic tools for specifically manipulating the fibroblast in vivo, the contribution ofthe fibroblast and myofibroblast to tissue repair and fibrotic disease has not been clearly defined. This proposal features two newly developed fibroblast-specific Cre knockin mouse models for delineating the fibroblast's role in myocardial repair and fibrosis and to identify the molecular regulators of the fibroblast-dependent fibrotic response. Currently, most studies examining the regulatory networks in myofibroblast transformation have been solely focused on TGF? signaling due to its central role in initiating myofibroblast transformation and fibrosis, providin a very limited scope of the regulatory networks driving the fibrotic process. This prompted us to perform a genome-wide screen for new molecular regulators of fibroblast to myofibroblast conversion from which we identified the gene for the RNA-binding protein muscleblind-like splicing regulator 1 (MBNL1). To date MBNL1 function has never been linked to tissue repair or fibrosis, but our preliminary data in primary fibroblasts (cardiac and MEFs) demonstrates that MBNL1 is both necessary and sufficient for inducing fibroblast to myofibroblast transformation, suggesting that MBNL1 is a primary mediator of fibrotic disease. Thus, this proposal is designed (1) to directly examine the mechanism by which injury induced changes in MBNL1's regulation of transcript abundance and alternative splicing alters the fibroblast's proteome to functionally transform into a myofibroblast and (2) to directly examine the role programmed fibroblast transformation by MBNL1 has in tissue repair and fibrotic disease. By defining the regulatory networks directing fibroblast to myofibroblast transformation this proposal will further delineate the cellular and molecular underpinnings for fibrotic disease which in turn should yield new invention points for developing targeted interventions and drug discovery as many of these molecular regulators should be amenable to pharmacologic remediation.
Cardiac fibrosis is a disease state that causes the heart to become scarred and function poorly, and as a result it is a primary contributor to progressive heart failure and sudden death, which accounts for almost 300,000 deaths annually in the United States. A specialized contractile and secretory cell called a myofibroblast is the primary initiator of cardiac fibrosis. This proposal seeks to understand the molecular and genetic basis for the development of myofibroblasts and hence the fibrotic response in the heart.
|Davis, Jennifer; Salomonis, Nathan; Ghearing, Natasha et al. (2015) MBNL1-mediated regulation of differentiation RNAs promotes myofibroblast transformation and the fibrotic response. Nat Commun 6:10084|
|Kwong, Jennifer Q; Lu, Xiyuan; Correll, Robert N et al. (2015) The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart. Cell Rep 12:15-22|
|Liu, Ruijie; Correll, Robert N; Davis, Jennifer et al. (2015) Cardiac-specific deletion of protein phosphatase 1? promotes increased myofilament protein phosphorylation and contractile alterations. J Mol Cell Cardiol 87:204-13|
|Davis, Jennifer; Molkentin, Jeffery D (2014) Myofibroblasts: trust your heart and let fate decide. J Mol Cell Cardiol 70:9-18|
|Goonasekera, Sanjeewa A; Davis, Jennifer; Kwong, Jennifer Q et al. (2014) Enhanced Ca²? influx from STIM1-Orai1 induces muscle pathology in mouse models of muscular dystrophy. Hum Mol Genet 23:3706-15|
|Correll, Robert N; Eder, Petra; Burr, Adam R et al. (2014) Overexpression of the Na+/K+ ATPase ?2 but not ?1 isoform attenuates pathological cardiac hypertrophy and remodeling. Circ Res 114:249-256|
|Kwong, J Q; Davis, J; Baines, C P et al. (2014) Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy. Cell Death Differ 21:1209-17|
|Davis, Jennifer; Kwong, Jennifer Q; Kitsis, Richard N et al. (2013) Apoptosis repressor with a CARD domain (ARC) restrains Bax-mediated pathogenesis in dystrophic skeletal muscle. PLoS One 8:e82053|