Monday, May 6, 2024
5/6/2024
Abstract During early cardiac development, mitochondrial biogenesis and maturation occur at prenatal stages, so as to allow newborns to generate ATP relying on mitochondrial oxidative phosphorylation (OXPHOS). The gene- regulatory mechanisms controlling mitochondrial biogenesis during early development stages is not well- understood, leading to difficulties in predicting pediatric cardiomyopathies due to mitochondrial dysfunction. The long-term goal of this proposed study is to understand the relationship between transcriptional regulation and metabolism in the cardiovascular system. Research conducted in our laboratory revealed that GATA4 binds to regulatory DNA regions to regulate the expression of PPARGC1A (encoding PGC-1a), which serves as an important regulator of mitochondrial biogenesis and maturation. We also demonstrated that overexpression of GATA4 can rescue mitochondrial function and biogenesis in cardiomyocytes that were impaired from cancer drug exposure; and repression of GATA4 decreased mitochondrial respiration in cardiomyocytes. Our central hypothesis is that GATA4 is involved in mitochondrial biogenesis via regulation of PPARGC1A during early cardiac development. The rationale is that as both GATA4 and mitochondria- dependent metabolism that are two essential factors controlling cardiac development, there is a critical need to understand how GATA4 regulates mitochondrial biogenesis. In the proposed study, we will combine a scaffold- free 3D-cardiac organoid method with CRISPR/dCas9-interference approaches as a novel system to test our central hypothesis; we will also use transgenic mice to validate the results. The central hypothesis will be tested by pursuing the following specific aims: 1) Investigate the dynamic alterations in metabolic profiles and mitochondrial biogenesis during cardiac differentiation after modulation of GATA4 expression, 2) Investigate the mechanisms that govern GATA4 regulation of PPARGC1A and GATA4-mediated regulatory networks during early cardiac differentiation, and 3) Investigate alterations in cardiac metabolic profiles and mitochondrial biogenesis in transgenic Gata4-mutant mouse embryos and neonates. The innovation of this study is that we will use a novel system to investigate mechanisms during early cardiac development, as well as integrating computational biology and single-cell multi-omics. The proposed study is significant because it will reveal mechanisms underlying GATA4-mediated transcriptional regulation in metabolism during cardiac development. We expect to determine regulatory roles for GATA4 in mitochondrial biogenesis. The positive impacts of this study include: 1) filling the gaps in our understanding of early-onset cardiac defects from the dysregulation of metabolism due to dysfunction of GATA4; 2) improving therapeutic intervention for pediatric cardiomyopathies from metabolic disorders; 3) providing an excellent opportunity to transfer our experience and expertise to graduate and undergraduate students.
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