THE CONTRIBUTION OF SMC TO THE PATHOLOGY OF GASTROINTESTINAL STROMAL TUMORS

SMC 对胃肠间质瘤病理学的贡献

• 批准号: 7720098
• 负责人: Lucy Liaw
• 金额: $ 18.87万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720098
• 关键词: Address; Biological Markers; Cell Cycle Progression; Cell Differentiation process; Computer Retrieval of Information on Scientific Projects Database; Differentiation Antigens; Differentiation Therapy; Equilibrium; Feedback; Funding; Gastrointestinal Stromal Tumors; Gene Targeting; Genetic Transcription; Grant; Growth; Human; Institution; Mediating; Molecular; Normal Cell; Pathology; Phenotype; Regulation; Research; Research Personnel; Resources; Signal Transduction; Smooth Muscle Myocytes; Source; Tumor Pathology; United States National Institutes of Health; Vascular remodeling; Viral; base; gamma secretase; inhibitor/antagonist; neoplastic cell; notch protein; novel; transduction efficiency

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. Activation of Notch signaling in human SMC was accomplished with adenoviral transduction of constitutively active intracellular domain forms of the Notch receptors. Secondly, expression of the Notch target genes, HRT1 and HRT2, was used to understand the functions of these bHLH factors in Notch-mediated SMC regulation. Analysis of SMC differentiation marker expression, transcription, turnover, and stability determined that Notch provides a strong signal for the SMC differentiated phenotype. Surprisingly, however, HRT activity antagonizes Notch signaling, and suppresses the SMC differentiated phenotype. These findings provide the framework for a novel Notch negative feedback mechanism that may serve to regulate the balance between the mature phenotype and the transitional phenotype necessary for vascular remodeling.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目基于观察结果，即Notch信号传导是平滑肌细胞（SMC）分化和细胞周期进程的重要调节剂，而胃肠道肿瘤（GIST）与SMC共享分子标记。人GIST细胞表达缺口受体，其生长受到阻断内源性缺口信号传导的γ泌尿酶抑制剂的抑制。与要点重点相关的挑战是：信号研究的病毒转导效率有限，直到最近，只有一个分离的要点细胞的可用性。因此，在最后一个资金期间，我们主要关注人类主要SMC，以解决Notch信号传导调节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这样的观点，即与要点有关的细胞分化疗法可能是阻止GIST病理异常生长和进展的一种机制。人类SMC中Notch信号传导的激活是通过腺病毒的腺病毒转导的Notch受体的组成型细胞内结构域形式来完成的。其次，使用Notch靶基因HRT1和HRT2的表达来理解这些BHLH因子在Notch介导的SMC调控中的功能。 SMC分化标记表达，转录，周转和稳定性的分析确定Notch为SMC分化表型提供了强信号。然而，令人惊讶的是，HRT活性会拮抗Notch信号，并抑制SMC分化的表型。这些发现为一种新型缺口反馈机制提供了一个框架，该机制可以调节成熟表型与血管重塑所需的过渡表型之间的平衡。