This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Activation of Notch receptor signaling in smooth muscle cells (SMC) leads to dysregulated cell cycle progression with features similar to cell transformation. We developed a highly innovative approach employing a gastrointestinal stromal tumor (GIST) model, to address fundamental issues surrounding smooth muscle cell development and differentiation. While the GIST is not thought to be a pure SMC tumor, this is a unique differentiation model because transformation potentially occurs in a precursor cell that gives rise to both SMC and cells of Cajal. GIST express smooth muscle actin and desmin and are characterized by activated c-kit. This study will test a model whereby c-kit activation leads to regulation of Notch signaling, which in turn impacts p27 and cell cycle progression. This project will benefit from collaborative interactions with B. Eisenberg, (Dartmouth), D. Wojchowski (MMCRI) and A. Godwin (Fox Chase Cancer Center). Projects 1 and 2 will be highly interactive since Cthrc1 may be a marker for GIST and play a regulatory role in invasion and angiogenesis. In addition, interaction with Project 3 (C. Vary) is anticipated since this project will be investigating blood vessel recruitment, which will be relevant to GIST angiogenesis. Interactions with R. Friesel are expected since the Spry and Spred family of Ras pathway inhibitors are likely to impact the c-kit pathway. Lastly, an anticipated interaction is expected with Project 4 (I. Prudovsky) studying inflammatory reactions of GIST. This project will utilize all cores and interact highly with Project 6, using MRI to monitor GIST tumor phenotype non-invasively.
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