THE CONTRIBUTION OF SMC TO THE PATHOLOGY OF GASTROINTESTINAL STROMAL TUMORS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本项目是基于Notch信号是平滑肌细胞(SMC)分化和细胞周期进程的重要调节因子，以及胃肠道间质瘤(GIST)与SMC共享分子标志物。人GIST细胞表达Notch受体，其生长受到伽马分泌酶抑制剂的抑制，从而阻断内源性Notch信号。与GIST焦点相关的挑战是：信号研究的病毒转导效率有限，而且直到最近，GIST细胞只有一个分离株可用。因此，在上一个资助阶段，我们主要集中在人类原代SMC，以探讨Notch信号调节SMC分化表型的基本分子机制。我们在正常细胞中的发现将应用于与GIST相关的细胞分化治疗可能是阻止GIST病理异常生长和进展的一种机制。今年的进展揭示了Notch信号和TGFbeta信号在SMC分化表型控制中的有趣的协同作用。这两条途径都激活了分化的表型，它们共同发挥协同作用。我们正在研究两个潜在的模型：第一，Notch通过调节TGFbeta共受体endoglin的表达来增加TGFbeta信号，第二，Notch直接与SMC中的Smads相互作用，改变Smad介导的转录。这些相互作用正在使用原代人类SMC在分子水平上进行测试。

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.