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Fibroblast Growth Factor (FGF) Signaling in Vertebrate Development Fibroblast growth factors represent a large family of secreted molecules that serve critical functions during embryogenesis. Aberrant FGF signaling has been frequently associated with the development of cancers and congenital skeletal defects. The lab is interested in how FGF signaling is controlled to ensure proper signaling levels are achieved during embryogenesis. We have been studying how FGF signaling is attenuated by both negative and positive feedback loops. The lab has focused on Dual Specificity Phosphatases (Dusp6), Sef, and members of the Pea3 Ets Transcription Factors (Etv4, Etv5a and Etv5b) as regulators of FGF signaling. Our future goal is to understand how these factors modulate FGF activity at a molecular level and how fine tuning of FGF signaling is critical for proper development.
We have generated a number of transgenic reporter lines that serve as a live read-out of FGF activity in the zebrafish embryo. Using Tg(Dusp6:d2EGFP) embryos we have successfully identified a small molecule, BCI that enhances FGF signaling. We have demonstrated that BCI is an allosteric inhibitor of Dusp6 and that treatment of zebrafish embryos during early somitogenesis stages can expand cardiac progenitors. Our future goal is to develop and implement automated whole organism chemical screens to identify novel modulators of the FGF/RAS/MAPK pathway. The tools we develop could in the future be applied to other signaling pathways and systems.
We have initiated studies on cardiac regeneration using a proteomics approach. The central question is whether small molecules that enhance FGF signaling can improve cardiac repair. With this in mind our initial goal is to identify novel markers of cardiac regenerations. From a proteomics analysis, we have identified several proteins that are upregulated during heart regeneration and we are exploring their role in cardiac repair. With these markers, it will be possible to determine if FGF activators can enhance the regenerative process and in the future apply these findings into mammalian systems.
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