Exploring the Role of Drp1 in Colorectal Cancer

探索 Drp1 在结直肠癌中的作用

• 批准号: 10591498
• 负责人: Sumati Raj Hasani
• 金额: $ 1.52万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-07-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10591498
• 关键词: Acetylation; Animal Model; Biochemical; Biochemistry; Bioenergetics; Cancer Center; Cancer Etiology; Cancer Model; Cell Communication; Cell Survival; Cellular biology; Cessation of life; Colon Carcinoma; Colorectal Cancer; Committee Members; Consumption; Data; Development; Disease; Down-Regulation; Environment; Fatty Acids; Fatty acid glycerol esters; Goals; High Fat Diet; Homeostasis; Image; Immunofluorescence Immunologic; Immunoprecipitation; Incidence; Kentucky; Knock-out; Knockout Mice; Knowledge; Malignant Neoplasms; Mediating; Mentors; Metabolic; Metabolic Pathway; Mitochondria; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mus; Nuclear; Obesity; Organelles; Organoids; Phosphorylation; Play; Property; Regulation; Research; Risk Factors; Role; Signal Pathway; Signal Transduction; Site; Stress; Testing; Tissues; Training; Tumor Promotion; United States; Universities; Up-Regulation; WNT Signaling Pathway; Western Blotting; beta catenin; cancer cell; cancer stem cell; cancer type; career; epidemiology study; experience; experimental study; fatty acid metabolism; fatty acid oxidation; in vivo; insight; mitochondrial fitness; mitochondrial metabolism; mortality; mouse model; novel; novel therapeutics; personalized medicine; receptor; recruit; stem cell function; tumor; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis; uptake; western diet

Abstract - Exploring the Role of Drp1 in Colorectal Cancer. Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately 150,000 new cases and 50,000 deaths are predicted for the year 2020. Emerging research suggests that the dysregulation of mitochondrial fitness due to an imbalance in mitochondrial dynamics can lead to metabolic reprogramming in various cancer types. A number of epidemiological studies indicate that obesity is as a major risk factor for several types of cancer including colorectal cancer. Our group and others have shown that increased uptake of fatty acids promotes the development and progression of difference cancers by altering metabolic pathways to favor mitochondrial fatty acid oxidation. However, the molecular mechanisms by which fatty acid consumption influences mitochondrial fitness to promote tumor cell survival and progression is poorly understood. In this proposed study, I plan to investigate the signaling crosstalk between mitochondrial dynamics and fatty acid metabolism in colorectal cancer. In my preliminary experiments, I discovered that fatty acid uptake promotes mitochondrial fragmentation by activating Drp1, a small GTPase required for mitochondrial fission, by increasing the phosphorylation at the S616 site and its interaction with mitochondria. Importantly, silencing Drp1 inhibits cancer stem cell functions by attenuating Wnt signaling in colon cancer cells. The central hypothesis is that Drp1-dependent mitochondrial fission is required for fatty acids to promote tumor progression in colon cancer. Specifically, I will determine how fatty acid uptake alters Drp1 activity and how mitochondrial dynamics augments cancer stem cell functions to drive tumorigenesis in vivo. The following specific aims are proposed: 1) to delineate the molecular mechanism by which fatty acid uptake enhances Drp1 activity; 2) to determine the functional importance of Drp1 in promoting CSC functions in colorectal cancer; and 3) to define the role of Drp1 in regulating tumorigenesis using in vivo colon cancer models. Results from this study will provide novel insights into the role of mitochondrial dynamics in connecting cellular metabolic pathways with cancer stem cell signaling. Dr. Gao has extensive experience in studying the regulation of signaling pathways and mitochondrial metabolism in colorectal cancer. I will also benefit from additional expertise provided by my committee members and state- of-the-art facilities of the Markey Cancer Center at the University of Kentucky. A comprehensive training plan has been developed to fit my research background and career goals. Based on my strong preliminary data, with my mentor’s knowledge and training, and the excellent research environment at the Department of Molecular and Cellular Biochemistry and the Markey Cancer Center I am confident that this project will be successful. Ultimately, this study will help develop personalized treatment options by targeting mitochondrial dynamics to eradicate cancer stem cells.

摘要-探索Drp 1在结直肠癌中的作用。 结直肠癌是美国癌症相关死亡的第二大原因。约 预计到2020年将有15万例新病例和5万例死亡。新的研究表明， 由于线粒体动力学的不平衡而引起的线粒体适应性的失调可导致代谢紊乱， 在各种癌症类型中的重编程。一些流行病学研究表明，肥胖是一个主要的 包括结肠直肠癌在内的几种癌症的风险因素。我们的团队和其他人已经证明， 增加脂肪酸的摄取通过改变脂肪酸的浓度来促进不同癌症的发展和进展。 代谢途径，有利于线粒体脂肪酸氧化。然而， 脂肪酸消耗影响线粒体适应性，以促进肿瘤细胞存活和进展， 明白在这项研究中，我计划研究线粒体动力学之间的信号串扰， 和脂肪酸代谢。在我的初步实验中，我发现脂肪酸的摄取 通过激活Drp 1（线粒体分裂所需的一种小GT3）促进线粒体碎片化， 增加S616位点的磷酸化及其与线粒体的相互作用。重要的是，沉默Drp 1 通过减弱结肠癌细胞中的Wnt信号传导来抑制癌症干细胞功能。核心假设是 Drp 1依赖性线粒体分裂是脂肪酸促进结肠肿瘤进展所必需的 癌具体来说，我将确定脂肪酸摄取如何改变Drp 1活性，以及线粒体动力学如何改变Drp 1活性。 增强癌症干细胞功能以驱动体内肿瘤发生。建议的具体目标如下： 1)阐明脂肪酸摄取增强Drp 1活性的分子机制; 2）确定 Drp 1在促进结肠直肠癌CSC功能中的功能重要性; 3）确定Drp 1的作用 在使用体内结肠癌模型调节肿瘤发生方面。这项研究的结果将提供新的见解 线粒体动力学在连接细胞代谢途径与癌症干细胞信号传导中的作用。 博士Gao在研究信号通路和线粒体代谢的调节方面具有丰富的经验 结肠直肠癌。我还将受益于我的委员会成员和国家提供的额外专业知识- 肯塔基州大学马基癌症中心最先进的设施。全面的培训计划 是为了适应我的研究背景和职业目标而开发的。根据我的初步数据， 我的导师的知识和培训，以及分子系优良的研究环境， 和细胞生物化学和马基癌症中心，我相信这个项目会成功。 最终，这项研究将有助于通过靶向线粒体动力学， 根除癌症干细胞