The zebrafish is an important genetic model for studying embryonic patterning and organogenesis. Although genetic tools are available to probe gene function and signaling pathways during embryonic development, their utility is limited with temporally tightly controlled processes or with genes whose perturbation results in embryo lethality. Small molecule probes can overcome these obstacles due to their rapid and reversible actions, thereby enhancing genetic studies and offering a unique opportunity to uncover the roles of signaling pathways in larval and adult physiology. Currently, methods to study gene function in adult zebrafish involves the generation of transgenic heat shock driver lines, the use of binary gene activation such as the Gal4-UAS system, or the use of genetic recombination such as Cre recombinase to activate gene expression. Sophisticated tissue specific gene knockouts are not currently feasible in zebrafish, thus limiting the study of signaling pathways to early development, when gene products can be knocked-down with antisense oligonucleotides. The objective of this proposal is to identify novel small molecule modulators of the FGF and TGFb pathways as tools to dissect the role of these signaling pathways in zebrafish larval and adult repair and regeneration. The FGF and TGFb signaling pathways are critical in regeneration, repair, and wound healing but their exploitation as potential pharmacological targets awaits elucidation of their precise molecular mechanisms during these events. Small molecules that hyper-activate these pathways would be useful tools to study the roles of these pathways and represent starting points for the development of novel regenerative therapies. Ultimately, we will provide the zebrafish community with a unique set of tools to study later stages of development and adult zebrafish models of disease. These studies will provide validated probes for enhancing FGF and TGFb signaling with defined specificity and in vivo activity in models of tissue repair and regeneration. The proposed work is divided into three specific aims, which take advantage of the complementary expertise of investigators on this multi-PI proposal.
Aim 1 : We will identify compounds that activate the FGF signaling pathway.
Aim 2 : We will identify compounds that activate the TGFb signaling pathway.
Aim 3 : We will test the efficacy of the new compounds in regeneration models that are commonly used in our laboratories.

Public Health Relevance

The objective of this proposal is to identify novel small molecule modulators of the FGF and TGFb pathways as tools to dissect the role of these signaling pathways. One major obstacle associated with studying zebrafish regeneration in larvae and adults is the limited number of means to functionally suppress or enhance these pathways in this process. To overcome these shortcomings, treatment with small molecules that suppress or enhance these signaling pathways is a desired approach. The ultimate goal is to provide the zebrafish community with unique set of instruments for studying the FGF and TGFb signaling pathways.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CB-Z (55))
Program Officer
Javois, Lorette Claire
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Cirio, M Cecilia; de Groh, Eric D; de Caestecker, Mark P et al. (2014) Kidney regeneration: common themes from the embryo to the adult. Pediatr Nephrol 29:553-64
Novitskaya, Tatiana; McDermott, Lee; Zhang, Ke Xin et al. (2014) A PTBA small molecule enhances recovery and reduces postinjury fibrosis after aristolochic acid-induced kidney injury. Am J Physiol Renal Physiol 306:F496-504
Korotchenko, Vasiliy N; Saydmohammed, Manush; Vollmer, Laura L et al. (2014) In vivo structure-activity relationship studies support allosteric targeting of a dual specificity phosphatase. Chembiochem 15:1436-45
Sanker, Subramaniam; Cirio, Maria Cecilia; Vollmer, Laura L et al. (2013) Development of high-content assays for kidney progenitor cell expansion in transgenic zebrafish. J Biomol Screen 18:1193-202
Cianciolo Cosentino, Chiara; Skrypnyk, Nataliya I; Brilli, Lauren L et al. (2013) Histone deacetylase inhibitor enhances recovery after AKI. J Am Soc Nephrol 24:943-53
Saydmohammed, Manush; Vollmer, Laura L; Onuoha, Ezenwa Obi et al. (2011) A high-content screening assay in transgenic zebrafish identifies two novel activators of fgf signaling. Birth Defects Res C Embryo Today 93:281-7
Hukriede, Neil A; Dawid, Igor B (2011) Making a tubule the noncanonical way. J Am Soc Nephrol 22:1575-7
Farrell, Thomas C; Cario, Clinton L; Milanese, Chiara et al. (2011) Evaluation of spontaneous propulsive movement as a screening tool to detect rescue of Parkinsonism phenotypes in zebrafish models. Neurobiol Dis 44:9-18
Vogt, Andreas; Codore, Hiba; Day, Billy W et al. (2010) Development of automated imaging and analysis for zebrafish chemical screens. J Vis Exp :
Swanhart, Lisa M; Takahashi, Nobuhiro; Jackson, Rachel L et al. (2010) Characterization of an lhx1a transgenic reporter in zebrafish. Int J Dev Biol 54:731-6

Showing the most recent 10 out of 14 publications