This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project is based on the observations that Notch signaling is an important regulator of smooth muscle cell (SMC) differentiation and cell cycle progression, and that gastrointestinal stromal tumors (GIST) share molecular markers with SMC. Human GIST cells express Notch receptors, and their growth is inhibited by gamma secretase inhibitors that block endogenous Notch signaling. Challenges associated with the GIST focus are: limited viral transduction efficiency for signaling studies, and until recently, the availability of only one isolate of GIST cells. Therefore, in the last funding period, we focused mainly on human primary SMC to address basic molecular mechanisms by which Notch signaling regulates SMC differentiation phenotypes. Our findings in normal cells will be applied to the idea that cell differentiation therapies related to GIST may be one mechanism to stop abnormal growth and progression of GIST pathologies. Progress this year uncovered an interesting synergistic interaction between Notch signaling and TGFbeta signaling in the control of SMC differentiation phenotype. Both pathways activate the differentiated phenotype, and together they synergize. We are studying two potential models: first, that Notch increases TGFbeta signaling by regulating the expression of endoglin, a TGFbeta co-receptor, and second, that Notch directly interacts with Smads in SMC, changing Smad-mediated transcription. These interactions are being tested at the molecular level using primary human SMC.
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