The Functional Role of GRM3 in Colon Cancer

项目总结/摘要 结直肠癌是癌症死亡率的第二大原因，也是诊断的第三大常见癌症 在美国，主要是由于转移，复发和耐药性。因此迫切 需要确定新的靶点并开发新的靶点特异性疗法。我们之前的研究表明， GRM 3是一种代谢型谷氨酸受体，主要表达于哺乳动物中枢神经系统， 在大多数测试的人结肠腺癌和结肠腺癌中， 癌细胞系。结肠癌细胞中GRM 3表达的敲低降低了细胞存活和锚定- 在体外独立生长并在体内抑制肿瘤生长。从机制上讲，GRM 3拮抗TGFβ- 介导的蛋白激酶A活化和AKT抑制。作为一名拥有10年经验的长期研究人员 和专长在结肠癌研究的王晶博士实验室，我将继续对这个项目的工作，以了解 TGFβ介导GRM 3表达的机制，确定GRM 3在结肠癌中的功能作用 使用原位和遗传小鼠模型， 结肠癌GRM 3表达及TGFβ/GRM 3相互作用的临床意义 患者样本。有了这个奖项的支持，这些研究的完成将确定TGFβ/GRM 3/PKA作为一个新的研究领域。 调节结肠癌发展和进展的新信号传导轴，并将GRM 3确立为潜在的 结肠癌治疗的治疗靶点。此外，我还将继续与 研究人员内外的NCI资助的研究计划，并承担责任， 指导和培训学生和博士后这个拟议的项目。

Project Summary/Abstract Colorectal cancer is the second leading cause of cancer mortality and the third most common cancer diagnosed in the United States, largely due to metastasis, recurrence and drug resistance. Therefore, there is an urgent need to identify new targets and develop novel target-specific therapies. Our previous study has shown for the first time that expression of GRM3, a metabotropic glutamate receptor mainly expressed in mammalian central nervous system, is significantly upregulated in the majority of human colonic adenocarcinomas tested and colon cancer cell lines. Knockdown of GRM3 expression in colon cancer cells reduces cell survival and anchorage- independent growth in vitro and inhibits tumor growth in vivo. Mechanistically, GRM3 antagonizes TGFβ- mediated activation of protein kinase A and inhibition of AKT. As a long-term researcher with 10 year experience and expertise in colon cancer research in Dr. Jing Wang lab, I will continue to work on this project to understand the mechanisms of TGFβ-mediated GRM3 expression, determine the functional role of GRM3 in colon cancer development, progression and metastasis in vivo using orthotopic and genetic mouse models and demonstrate clinical relevance and significance of elevated GRM3 expression and TGFβ/GRM3 crosstalk in colon cancer patient samples. With this award support, the completion of these studies will identify TGFβ/GRM3/PKA as a novel signaling axis regulating colon cancer development and progression and establish GRM3 as a potential therapeutic target for colon cancer treatment. Additionally, I will also continue to contribute to collaborations with researchers inside and outside of university in NCI funded research programs and take responsibilities in mentoring and training students and postdocs this proposed project.