Probing the Cardiac PGC-1 Regulatory Cascade

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SUMMARY During the fetal to adult transition, the heart undergoes dramatic developmental maturation. Following birth, many cardiac myocyte processes undergo transformation to adult programs including mitochondrial capacity, fuel utilization pathways, and the contractile machinery. Whereas, considerable progress has been made in defining the gene regulatory and signaling events involved in early cardiac development and morphogenesis, the mechanisms involved in postnatal cardiac developmental maturation are poorly understood. Delineation of the circuitry driving cardiac myocyte maturation is relevant to heart disease given that during the development of heart failure, many metabolic and contractile processes shift to an immature or “fetal” state. In addition, a better understanding of the mechanisms driving cardiac myocyte maturation will provide new strategies for enabling full maturation of human induced-pluripotent stem cells into adult cardiac myocytes in experimental systems including proof-of-concept therapeutic studies. Our recent work has shown that the nuclear receptors ERR and, central effectors of the PGC-1 transcriptional regulatory circuit, are key drivers of mitochondrial biogenesis and maturation during postnatal cardiac development, and in the adult heart. Very recently, we found that the ERRs are not only regulators of mitochondrial maturation, but are also necessary for postnatal cardiac development. We seek to define the players and mechanisms involved in the broad program of postnatal cardiac maturation by starting with the PGC-1/ERR complex. This project is defined to test the novel hypothesis that the nuclear receptors ERR and, central components of the PGC-1-induced transcriptional regulatory circuit, function as key components of a broader cardiac maturation network. The proposed experimental plan, buttressed by preliminary data and reagents developed over the past two years of the current funding period, will employ a combination of state-of-the-art proteomics, functional genomics, in vivo studies in mice, and human heart tissue profiling. Using the ERR as an anchor nexus we will: 1) define the protein interaction network of transcriptional and epigenomic regulators that cooperate with the ERRs (ERR interactome) to orchestrate metabolic and non-metabolic cardiac myocyte gene target expression; 2) identify upstream factors and signals that trigger activation of the PGC-1/ERR circuitry during cardiac maturation; and 3) determine how this network shifts toward the fetal state during development of heart failure, and assess the potential of its re-activation to ameliorate pathological cardiac remodeling in pre-clinical heart failure models. The planned studies will lead to important new insights into the mechanisms whereby the fetal heart transforms into the adult heart and will provide in-depth, pre-clinical, assessment of the potential of re-activating cardiac myocyte maturation as a novel therapeutic for heart failure.