Investigating the role of mutation sequence and microRNAs in colorectal cancer de

描述（由申请人提供）：众所周知，遗传和表观遗传改变在结直肠癌（CRC）的发生和进展中起重要作用。我们理解这一过程如何发生的一个主要挑战是理解这些遗传和表观遗传变化如何在病理上起作用，从而允许不受控制的癌细胞生长。到目前为止，控制CRC起始和进展的信号通路和基因的系统解剖受到原发性人类肿瘤样本的使用，缺乏合适的长期培养系统以及不能准确重现这一过程的小鼠模型的限制。我们小组最近开发了一种能够模拟肿瘤发生的稳定的长期原代结肠上皮培养系统，这为开始分别探索癌基因和抑癌基因激活或失活的差异序列的作用以及CRC上调或下调的microRNA在CRC发展中的功能评估提供了机会。具体而言，该提案旨在解决一个假设，即获得遗传改变的序列会改变CRC进展，并可能改变临床结果。同样，该提议试图在功能上验证在CRC与正常人结肠上皮中差异表达的microRNA的作用。本文提出的研究将促进我们对结肠癌发生和进展的基本理解，从而开发更有效和更有针对性的治疗方法。 公共卫生相关性：结直肠癌是一种多样性和异质性的疾病，是由遗传和表观遗传改变的进行性积累引起的。健康差异和不同的临床结果可以部分归因于特定肿瘤内发生的特定遗传改变。了解基因功能的改变，或获得它们的序列，以及microRNA表达的变化如何促进结直肠癌的发展，将提供新的见解，有助于我们开发更好的治疗方法，疗法和/或诊断工具。

DESCRIPTION (provided by applicant): It is well established that genetic and epigenetic alterations play important roles in the initiation and progression of colorectal cancer (CRC). A major challenge to our understanding of how this process occurs is to understand how these genetic and epigenetic changes work pathologically to allow for uncontrolled cancer cell growth. Until now, the systematic dissection of the signaling pathways and genes that control CRC initiation and progression have been limited by the use of primary human tumor samples, lack of suitable long-term culture systems, and mouse models that do not accurately recapitulate this process. The recent development of a robust long-term primary colonic epithelium culture system by our group that is capable of modeling tumorigenesis affords the opportunity to begin to explore the role of differential sequence of oncogene and tumor suppressor gene activation or inactivation, respectively, and the functional evaluation of CRC-upregulated or downregulated microRNAs in the development of CRC. Specifically, this proposal seeks to address the hypothesis that the sequence in which one acquires genetic alterations alters CRC progression, and possibly clinical outcomes. Likewise, this proposal seeks to functionally validate the role of microRNAs that are differentially expressed in CRC vs. normal human colonic epithelium. The studies proposed herein will facilitate our fundamental understanding of colon cancer initiation and progression, allowing for the development of more efficacious and targeted approaches to therapy. PUBLIC HEALTH RELEVANCE: Colorectal Cancer is a diverse and heterogeneous disease that is caused by the progressive accumulation of genetic and epigenetic alterations. Health disparities and diverse clinical outcomes can be partially attributed to the specific genetic alteration that occurs within a specific tumor. Understanding how alterations in gene function, or the sequence in which one acquires them, and how changes in microRNA expression contribute to colorectal cancer development will provide novel insights that will contribute to our ability to develop better treatments, therapies, and/or diagnostic tools.