There are multiple pathways leading to heart failure, the leading cause of death in man. Human dilated cardiomyopathy (DCM) mutations occur in genes encoding proteins with contractile functions, in proteins involved in force transmission, in proteins of the cytoskeleton, in one nuclear membrane protein, in proteins involved in Ca2+ homeostasis and in a protein involved in transcriptional regulation. These data clearly indicate that definition of all genetic causes of human DCM while still an informative approach for identifying the inciting molecular trigger for remodeling and heart failure will be very laborious. Another approach for addressing this problem is to define the pathways triggered by distinct gene mutations. This approach has several advantages. First information about these signaling pathways has the potential for defining nodal points that may be activated in several DCM genes and non-genetic causes of heart failure. Second, understanding components of these pathways should provide mechanistic insights into ventricular remodeling that may suggest novel therapeutic approaches to attenuate progression to heart failure. Finally, definition of components of these pathways should provide a wealth of candidate disease genes that may also be primary causes of ventricular remodeling and heart failure. While recognizing there are likely multiple pathways leading from a DCM gene mutation to ventricular remodeling and heart failure, we propose to study two: the pathway activated by mutation of a transcription co-factor Eya4 and the pathway activated by a dominant phospholamban (PLN) mutation. The Eya4 disease gene was selected to allow study of transcriptional signals that remodel the heart. The PLN mutation was selected to allow study of how disturbed calcium cycling, a fundamental process in cardiac physiology, causes heart failure. The pathways triggered by these two human DCM genes will be explored through specific aims that will: 1) Characterize cardiac pathophysiology in Eya4-deficient (Eya4+/-) mice. 2) Define the downstream target genes regulated by Eya4 in the heart. 3) Assess which Eya4-responsive genes contribute to DCM. 4) Characterize the histopathology of PLN R9C-induced ventricular remodeling and assess reversibility. 5) Define changes in transcriptome and proteome in PLN R9C hearts. 6) Assess the primacy of PLN R9C-altered proteins in DCM and heart failure.
| Patel, Parth N; Gorham, Joshua M; Ito, Kaoru et al. (2018) In vivo and In vitro methods to identify DNA sequence variants that alter RNA Splicing. Curr Protoc Hum Genet 97: |
| Sharma, Arun; Toepfer, Christopher N; Schmid, Manuel et al. (2018) Differentiation and Contractile Analysis of GFP-Sarcomere Reporter hiPSC-Cardiomyocytes. Curr Protoc Hum Genet 96:21.12.1-21.12.12 |
| Sharma, Arun; Toepfer, Christopher N; Ward, Tarsha et al. (2018) CRISPR/Cas9-Mediated Fluorescent Tagging of Endogenous Proteins in Human Pluripotent Stem Cells. Curr Protoc Hum Genet 96:21.11.1-21.11.20 |
| Garfinkel, Amanda C; Seidman, Jonathan G; Seidman, Christine E (2018) Genetic Pathogenesis of Hypertrophic and Dilated Cardiomyopathy. Heart Fail Clin 14:139-146 |
| Sharma, Arun; Mücke, Michael; Seidman, Christine E (2018) Human Induced Pluripotent Stem Cell Production and Expansion from Blood using a Non-Integrating Viral Reprogramming Vector. Curr Protoc Mol Biol 122:e58 |
| Eyckmans, Jeroen; Chen, Christopher S (2017) 3D culture models of tissues under tension. J Cell Sci 130:63-70 |
| Saddic, Louis A; Sigurdsson, Martin I; Chang, Tzuu-Wang et al. (2017) The Long Noncoding RNA Landscape of the Ischemic Human Left Ventricle. Circ Cardiovasc Genet 10: |
| Ito, Kaoru; Patel, Parth N; Gorham, Joshua M et al. (2017) Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing. Proc Natl Acad Sci U S A 114:7689-7694 |
| Alamo, Lorenzo; Ware, James S; Pinto, Antonio et al. (2017) Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes. Elife 6: |
| Schafer, Sebastian; de Marvao, Antonio; Adami, Eleonora et al. (2017) Titin-truncating variants affect heart function in disease cohorts and the general population. Nat Genet 49:46-53 |
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