The ASPIRE Path in Molecular Medicine

For my thesis work I have proposed to study the role of the SRY-related transcription factor, Sox17, in the development of the hepato-pancreato-biliary (HPB) system. In humans Sox17 variants are associated with congenital heart disease, cancer and malformations of endoderm derived organs. Thus far my lab has used an allelic series of Sox17 mutant mice to study the role of Sox17 in HPB development. We have found that minor reductions in Sox17 cause gallbladder hypoplasia, severe reductions results in gallbladder agenesis, and that complete loss of expression in mice is embryonic lethal. The overall conclusion from these studies is that the HPB system is exquisitely sensitive to the level of Sox17 expressed during development. In order to deepen our understanding of the sensitivity of the HPB system to Sox17 expression levels I have developed four novel mutant mouse lines. The ultimate goal is to expand upon our allelic series and further perturb Sox17 expression to specific levels allowing us to better understand the dependency of the HPB system, on specific concentrations of Sox17 for proper development. My hypothesis is that either overexpression or reductions in Sox17 will disrupt segregation of hepatic, pancreatic, and biliary progenitor cells resulting in specific concentration dependent HPB developmental abnormalities.