Exploiting metabolism to alter the epigenome of Cyclin E-altered ovarian cancer

利用代谢改变 Cyclin E 改变的卵巢癌的表观基因组

• 批准号: 9760441
• 负责人: Erika S Dahl
• 金额: $ 3.16万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760441
• 关键词: Accounting; Address; Affect; Binding; Biological Assay; CCNE1 gene; Cancer Patient; Carcinoma; Cell Cycle Arrest; Cell Cycle Progression; Citric Acid Cycle; Clinic; Clinical; Comet Assay; DNA Damage; Data; Decarboxylation; Development; Drug Targeting; Environment; Enzymes; Epigenetic Process; Epithelial ovarian cancer; Exhibits; Family; Family member; Future; Genes; Genetic Transcription; Goals; Greater sac of peritoneum; Healthcare; Histones; Isocitrate Dehydrogenase; Isocitrates; Knowledge; Lead; Luciferases; Malignant Epithelial Cell; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Medicine; Mentors; Metabolic; Metabolism; Modeling; National Research Service Awards; Omentum; Pathway interactions; Patients; Pennsylvania; Pharmacology; Phase; Phosphorylation; Play; Proteins; Publishing; Research; Research Personnel; Resources; Role; Seeds; Serous; Site; Stress; Techniques; Testing; Therapeutic; Training; Training Support; Tumor Burden; Universities; Up-Regulation; Xenograft procedure; alpha ketoglutarate; ataxia telangiectasia mutated protein; base; cancer cell; career; chromatin immunoprecipitation; cofactor; college; combat; demethylation; epigenome; histone demethylase; histone methylation; in vivo; knock-down; mouse model; mutant; novel; novel therapeutics; overexpression; promoter; response; senescence; skills; tumor

Project Summary The goals of this F31 NRSA are to request support for training to develop expertise in the progression of high- grad serous epithelial ovarian cancer while addressing a fundamental gap in knowledge that has the potential to significantly impact healthcare options for ovarian cancer patients. F31 Ruth L. Kirschstein NRSA support will highly impact this integral phase of my current scientific career and my future aspirations of becoming an independent academic researcher. The training plan described will utilize all relevant resources available at Penn State College of Medicine; as well as resources provided by my dynamic mentoring committee at Drexel University and University of Pennsylvania. The scientific portion of this proposal focuses on experimentally and mechanistically determining the role of metabolism and epigenetic modulation in cyclin E-altered high-grade serous carcinoma (HGSC) and whether this pathway can be targeted as a pro-senescent therapy in the clinic. The proposed studies are based on my robust preliminary data suggesting that TCA cycle enzyme, IDH1, is upregulated in epithelial ovarian cancer when compared to the fallopian tube, the potential site of HGSC origin. Additional preliminary data suggests that IDH1 is upregulated in order to increase transcription of DNA damage response gene, ataxia telangiectasia mutated (ATM) through histone methylation status, a topic of which I have previously published a review. Interestingly, my strong preliminary data also indicates that knockdown of IDH1 induces senescence. Therefore, in continuation of these robust preliminary data I will explore three scientific aims: 1) to determine the mechanism by which cyclin E upregulates IDH1 expression; 2) to investigate the role of IDH1 in the DNA damage response; and 3) to develop inhibition of IDH1 as a novel therapeutic strategy in cyclin E-altered HGSC. The completion of the proposed scientific aims will develop my research skills utilizing HGSC as a model in addition to increasing my independence as a scientific researcher. Conclusions drawn from the proposed studies may develop rationale for targeting IDH1 in cyclin E-altered HGSC clinically.

项目摘要 本F31 NRSA的目标是请求支持培训，以发展高级 格拉德浆液性上皮性卵巢癌，同时解决知识的根本差距，有可能 显著影响卵巢癌患者的医疗选择。F31露丝湖Kirschstein NRSA支持将 这对我目前的科学生涯和我未来成为一名 独立学术研究员。所述培训计划将利用所有相关资源， 宾夕法尼亚州立大学医学院;以及我在德雷克塞尔大学的动态指导委员会提供的资源 University of Pennsylvania. 该提案的科学部分侧重于实验和机械地确定 在细胞周期蛋白E改变的高级别浆液性癌（HGSC）中的代谢和表观遗传调节， 该途径可以作为临床中的促衰老疗法的目标。这些研究是基于我的 可靠的初步数据表明，TCA循环酶IDH 1在上皮性卵巢癌中上调， 与输卵管相比，输卵管是HGSC起源的潜在部位。额外的初步数据表明， IDH 1被上调以增加DNA损伤反应基因的转录，共济失调毛细血管扩张症 突变（ATM）通过组蛋白甲基化状态，一个主题，我以前发表了评论。 有趣的是，我强有力的初步数据也表明，IDH 1的敲低诱导衰老。 因此，在继续这些强有力的初步数据，我将探讨三个科学目标：1）确定 探讨细胞周期蛋白E上调IDH 1表达的机制; 2）研究IDH 1在DNA损伤中的作用 反应;和3）开发IDH 1的抑制作为细胞周期蛋白E改变的HGSC中的新的治疗策略。的 完成所提出的科学目标将发展我的研究技能，利用HGSC作为一个模型，此外 作为一名科学研究者，我的独立性得到了提高。从拟议研究中得出的结论可能 为临床上在细胞周期蛋白E改变的HGSC中靶向IDH 1提供理论依据。