Characterization of the role of STK38 kinase in Wnt signaling and heart development

Project Summary: This proposal seeks to study the relationship between STK38 kinase, Wnt signaling, and heart development, aiming to unravel STK38’s molecular mechanism with therapeutic implications for the treatment of congenital heart defects. The Wnt pathway plays a critical role in developmental processes such as heart development, and dysregulation of Wnt signaling has been linked to congenital heart defects. We have recently identified a new component of the Wnt pathway, STK38, and preliminary studies in zebrafish indicate that it plays a critical role in heart development. Through Aim 1, employing advanced techniques involving co-immunoprecipitation, mass spectrometry, and cellular labeling, I aim to identify STK38’s substrates within the Wnt signaling cascade. Characterizing these substrates and assessing their function will shed light on STK38's role as a regulator of Wnt signaling. Additionally, our preliminary studies suggest that STK38 interacts with Pygopus, a core nuclear Wnt component shown to play a role in vertebrate heart development, providing further evidence for the role of STK38 in Wnt signaling and cardiogenesis. This interaction will be characterized, which will aid in our understanding of STK38’s role in Wnt signaling. In Aim 2, I leverage induced pluripotent stem cells (iPSCs) as a powerful platform for modeling the progression from stem cells to cardiomyocytes. By monitoring endogenous STK38 levels during iPSC cardiac differentiation and correlating them with known periods of Wnt pathway activity, I will elucidate STK38's temporal expression dynamics during cardiac development. Furthermore, I will utilize iPSCs to chemically induce precise temporal depletion of STK38, enabling me to dissect STK38’s influence on Wnt signaling and cardiomyocyte differentiation/proliferation during critical periods of heart development. Through these complementary but non-overlapping aims, my research proposal seeks to advance our understanding of STK38's involvement in Wnt signaling and heart development. Successful completion of the grant holds promises for identifying novel therapeutic targets and enhancing our knowledge of congenital heart defects. In addition, this proposal will serve to greatly advance my knowledge and skills, propelling me forward toward my goal of becoming a successful academic researcher.