TRANSCRIPTION FACTORS IN INTESTINAL DIFFERENTIATION AND CANCER

肠道分化和癌症中的转录因子

• 批准号: 9976474
• 负责人: Yuan-Hung Lo
• 金额: $ 9.79万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976474
• 关键词: Basic Science; Biological; Cancer Biology; Cell Differentiation process; Cell Lineage; Cells; ChIP-seq; Chromatin; Collaborations; Colorectal Cancer; Communities; Competence; Core Facility; Custom; DNA sequencing; Digestion; Disease; ETS Domain; Education; Educational workshop; Electrolytes; Epithelial; Epithelial Cells; Epithelium; Family; Feedback; Gatekeeping; Genetic Transcription; Genomics; Goals; Goblet Cells; Homeostasis; Homologous Gene; Human; Intestinal Cancer; Intestinal Diseases; Intestinal Neoplasms; Intestines; Invaded; Knowledge; Large Intestine; Learning; Malignant Neoplasms; Mediating; Modeling; Molecular; Mucinous; Neoplasm Metastasis; Nutrient; Paneth Cells; Pathogenesis; Pathway interactions; Physiological; Play; Process; Public Health; Publications; Reporting; Research; Research Personnel; Research Project Grants; Role; Scientific Advances and Accomplishments; Secretory Cell; Signal Pathway; Signal Transduction; Small Intestines; Technical Expertise; Techniques; Testing; Therapeutic; Thinking; Tissues; Training; Transcriptional Regulation; Transgenic Mice; Tumor Suppression; Tumor Suppressor Proteins; Water; Wing; Work; absorption; anticancer research; base; beta catenin; cancer cell; cancer type; career; career development; colorectal cancer treatment; design; experimental study; extracellular; genome-wide; insight; intestinal epithelium; intestinal homeostasis; member; mouse model; neoplastic cell; notch protein; novel; novel therapeutics; progenitor; programs; protein protein interaction; skills training; stem cells; therapeutic target; transcription factor; transcriptome sequencing; tumor; tumor microenvironment; tumor progression; tumorigenesis

Colorectal cancer (CRC) is one of the most common and lethal cancers worldwide. Under physiological conditions, the Notch and Wing-less/Int (Wnt) signaling pathways modulate homeostasis and differentiation of the intestinal epithelium. In intestinal cancers, these pathways are frequently dysregulated. Canonical Wnt/β- catenin signaling pathway activation, with resultant high β-catenin transcriptional activity, is frequently implicated in human CRC; however, there are currently no treatments targeting this pathway. Several points of crosstalk between Notch and Wnt pathways have been described in CRC. Thus, uncovering the molecular mechanisms of transcriptional networks governed by the Notch and Wnt/β-catenin pathways in intestinal tumorigenesis is significant for advancing scientific knowledge on cancer biology, and would potentially provide a window for new CRC therapeutics. The long-term goal of the proposed research is to identify how transcriptional machinery controls intestinal cell differentiation and how critical transcription factors contribute to intestinal tumorigenesis. In Aims 1 and 2, using the novel transgenic mouse models and unbiased highthroughput RNA and DNA sequencing techniques, I have managed several parallel projects and multiinstitutional collaborations to understand the role of transcription factor Atoh1 (Atonal homolog 1), and its downstream target, SAM Pointed Domain ETS transcription Factor (SPDEF) in CRCs. The results from the proposed project are expected to significantly advance our current understanding of transcriptional machinery in CRCs. To extend my current knowledge and gain deeper insight into the biology of cancer, in Aim 3, I plan to pursue my postdoctoral studies in the direction of understanding how these extracellular components within the tumor microenvironment contribute to the program of cancer cell metastasis, a primary cause of cancerrelated fatality with CRCs, especially how these cells grow, invade, migrate, and resist treatment. Collectively, this training is customized to give me a comprehensive education in basic science research that will be extremely in achieving my long-term career goal of becoming an independent cancer researcher.

结直肠癌(CRC)是世界范围内最常见、最致命的癌症之一。在生理状态下 条件，Notch和无翼/Int(Wnt)信号通路调节细胞的动态平衡和分化 肠上皮细胞。在肠癌中，这些途径经常是不受调控的。规范的WNT/β- 连环蛋白信号通路的激活，伴随着高的β-连环蛋白转录活性，通常是 与人类结直肠癌有关；然而，目前还没有针对这一途径的治疗方法。以下几点 CRC中描述了Notch和Wnt路径之间的串扰。因此，揭开分子 肠道Notch和Wnt/β-Catenin通路调控转录网络的机制 肿瘤发生学对推进癌症生物学的科学知识具有重要意义，并可能提供 结直肠癌新疗法的窗口。拟议研究的长期目标是确定如何 转录机制控制肠道细胞分化和关键转录因子的作用 与肠道肿瘤的发生有关。在目标1和目标2中，使用了新的转基因小鼠模型和无偏见的高通量 RNA和DNA测序技术，我管理过几个并行项目和多个机构 合作了解转录因子Atoh1(无调性同源1)的作用，以及它的 下游靶点，SAM指向癌组织中的结构域ETS转录因子(SPDEF)。结果来自于 被提议的项目有望显著地推进我们目前对转录机制的理解 在CRC中。为了扩展我目前的知识并对癌症的生物学有更深入的了解，在目标3中，我计划 继续我的博士后研究，以了解这些细胞外成分是如何在 肿瘤微环境在癌细胞转移过程中起着重要作用，而癌细胞转移是癌症相关的主要原因 癌细胞的致死性，特别是这些细胞如何生长、入侵、迁移和抵抗治疗。总而言之， 这次培训是为了给我一个全面的基础科学研究教育，这将是 在实现我成为一名独立癌症研究人员的长期职业目标方面，我表现得非常出色。