Exploring the Role of Drp1 in Colorectal Cancer

摘要-探讨Drp1在结直肠癌中的作用。 在美国，结直肠癌是癌症相关死亡的第二大原因。大致 预计2020年新增病例15万例，死亡5万人。新出现的研究表明， 由于线粒体动力学失衡而导致的线粒体适合性失调可导致代谢 在各种癌症类型中重新编程。一些流行病学研究表明，肥胖是一种主要的 包括结直肠癌在内的几种癌症的危险因素。我们的团队和其他人已经证明 脂肪酸摄取增加通过改变改变促进不同癌症的发生发展 有利于线粒体脂肪酸氧化的代谢途径。然而，其分子机制 脂肪酸摄入影响线粒体适合性促进肿瘤细胞存活和进展较差 明白了。在这项拟议的研究中，我计划研究线粒体动力学之间的信号串扰 以及结直肠癌中的脂肪酸代谢。在我的初步实验中，我发现脂肪酸摄取 通过激活Drp1促进线粒体碎裂，Drp1是线粒体分裂所需的一种小GTP酶，通过 增加S616位点的磷酸化及其与线粒体的相互作用。重要的是，让Drp1沉默 通过减弱结肠癌细胞中的Wnt信号来抑制癌症干细胞的功能。中心假设是 依赖于Drp1的线粒体分裂是脂肪酸促进结肠肿瘤进展所必需的 癌症。具体地说，我将确定脂肪酸摄取如何改变Drp1的活性，以及线粒体动力学如何 增强癌症干细胞的功能，推动体内肿瘤的形成。提出了以下具体目标： 1)描述脂肪酸摄取增强DRp1活性的分子机制；2)确定 DRp1在促进结直肠癌CSC功能中的功能重要性；以及3)确定Drp1的作用 利用体内结肠癌模型调控肿瘤发生。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和癌症干细胞信号中的作用。 高博士在研究信号通路和线粒体代谢的调节方面有丰富的经验。 在结直肠癌方面。我还将受益于我的委员会成员和州政府提供的额外专业知识- 肯塔基大学马基癌症中心最先进的设施。全面的培训计划 是根据我的研究背景和职业目标而开发的。基于我强有力的初步数据， 我的导师的知识和培训，以及分子系良好的研究环境 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，这项研究将通过针对线粒体动力学来帮助开发个性化的治疗方案 根除癌症干细胞。

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.