Heart malformation is the leading cause of human birth defects and heart disease remains the number one killer of adults in the developed world. Recently, therapies based on multipotent cardiac progenitor cells (CPCs) have emerged as promising potential cardiac therapeutics. They can be purified from embryos or embryonic stem cell (ESC) systems and cultured to differentiate into various cardiac cell types including cardiomyocytes, smooth muscle and endothelial cells. However, the mechanisms underlying CPC self-renewal, proliferation and differentiation, a prerequisite for CPC-based cardiac therapy, are still emerging. I have demonstrated that Wnt/p-Catenin signaling is necessary and sufficient for CPC expansion after initial specification had occurred. I found several pivotal genes in CPC development that are negatively affected by |3-Catenin including Isletl, Myocd and Smydl. Notably, p-Catenin stabilization dramatically downregulated Isletl, a key regulatorof cardiogenesis that transiently marks undifferentiated CPCs. Correspondingly, Isletl-null embryos had an increased number of CPCs, suggesting that Isletl may be an important mediator of Wnt/p-Catenin signals in CPCs. Through use of mouse genetics and ESC systems, I found that Wnt/p-Catenin signaling functions as a central regulator of CPCs by integrating signals from Notchi and regulating a cascade of downstream transcriptional events involving Isll, Myocd and Smydl. These findings set the stage for an exploration ofthe role and the regulatory pathway of Isletl and Wnt/p-Catenin signaling in maintenance and differentiation of CPCs. I propose three specific aims. (1) To determine if Isletl affects the self-renewal, proliferation, and differentiation of CPCs. (2) To determine if Isletl is an essential effector for Wnt/p-Catenin signaling-mediated expansion of CPCs. (3) To determine if P-Catenin and Isletl are regulated by Notch signaling to mediate CPC expansion and differentiation.
This proposal is focused on elucidating the role and regulatory pathway of Wnt/p-Catenin signaling and Isletl for the expansion and differentiation of cardiac progenitors. These studies will lay the foundation for understanding the molecular mechanisms of cardiac progenitor cell development, which will accelerate future cell-based heart therapeutics.
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