Linking epigenetic regulation and TGF-β signaling in pancreatic cancer

连接胰腺癌中的表观遗传调控和 TGF-β 信号传导

• 批准号: 9977982
• 负责人: Jiaqi Shi
• 金额: $ 18.59万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-14 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977982
• 关键词: 3-Dimensional; Active Learning; Advisory Committees; Award; Basic Science; Bioinformatics; Bromouridine sequencing; Cancer Biology; Cancer Etiology; Cell Proliferation; Cessation of life; Clinical; Complex; Data; Databases; Development; Development Plans; Doctor of Philosophy; Educational workshop; Elements; Enhancers; Enzymes; Epigenetic Process; Epithelial Cells; Funding; Generations; Genes; Genetic; Goals; Grant; In Vitro; Investigation; K-Series Research Career Programs; Knowledge; Light; Link; MADH4 gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Mentors; Mentorship; Metastatic Neoplasm to Lymph Nodes; Michigan; MicroRNAs; Modification; Molecular; Mutation; Neoplasm Metastasis; Organoids; Pancreatic Adenocarcinoma; Pathology; Pathway interactions; Patients; Phenotype; Physicians; Play; Primary Neoplasm; Prognostic Marker; Publications; RNA chemical synthesis; Recording of previous events; Regulation; Research; Research Personnel; Role; Scientist; Signal Pathway; Signal Transduction; Survival Rate; System; TGFBR2 gene; Techniques; Technology; Testing; The Cancer Genome Atlas; Time; Training; Transcriptional Regulation; Transforming Growth Factors; Tumor Suppression; Tumor Suppressor Proteins; Universities; Work; Xenograft procedure; base; career development; diagnostic biomarker; epigenetic regulation; epigenomics; epithelial to mesenchymal transition; experience; genetic analysis; genome sequencing; histone modification; in vivo; lectures; loss of function mutation; migration; mouse model; novel; novel diagnostics; pancreatic cancer patients; prognostic; skills; symposium; therapeutic target; tumor growth; tumor progression; whole genome

Project Summary/Abstract Pancreatic adenocarcinoma (PDAC) is projected to be the second leading cause of cancer death in the US by 2020 with an overall five-year survival rate of <9%. Early metastasis is one of the main reasons for poor survival. Recent genome sequencing studies comparing primary tumor and metastases determined that similar mutations are present, but no specific metastasis drivers were identified. Thus, mechanisms responsible for tumor progression—and specifically for metastasis—require more investigation. Epigenomic regulation and epithelial to mesenchymal transition (EMT) are two important mechanisms for tumor progression and metastasis. We have discovered that miR455 links Transforming Growth Factor-β (TGF-β) and EMT signaling to histone modification. miR455 is upregulated by TGF-β, which in turn reduces the expression of KMT2D and KDM6A, two histone modification enzymes. Our data also revealed that increased miR455 or loss of KDM6A expression promoted PDAC cell EMT phenotype, migration, invasion, lymph node metastasis, and poor patient survival. In this proposal, we will define miR455-mediated novel cross talk between the TGF-β signaling and epigenetic modification in PDAC progression and metastasis. Our project will shed light on the poorly- understood epigenetic regulatory mechanisms in PDAC progression and metastasis, which will further contribute to the identification of new diagnostic and prognostic biomarkers and therapeutic targets. The overall goal of this application is to provide me more protected research time, obtain preliminary data and publication in the epigenetic research field, and develop new critical skills for me to become an R01-funded independent investigator in epigenetics and pancreatic cancer biology. The career development plan is based on formal courses, workshops, lectures, conferences, experiential learning and mentored basic science training. This K08 award and additional training is critical to my career development because of the basic science gap during my clinical training, the development of new knowledge and technologies in the field, and my current clinical duties. I have received generous support from my department and will work closely with my primary mentor, Dr. Yali Dou, PhD, an expert in epigenetics, and co-mentors Drs. Mats Ljungman, PhD, a leader in transcriptional regulation and bioinformatics, and Marina Pasca di Magliano, a leader in the pancreatic cancer field and expert in the generation and analysis of genetic mouse models. I have also constructed an advisory committee to further support my development as a successful physician scientist. I will devote at least 75% of my time to basic scientific research. The University of Michigan and Department of Pathology has a distinguished history in the training of independent cancer researchers. Together, the elements of this proposal will provide me with the experience, training, and mentorship needed to become a successful independent physician-scientist in the field of epigenetics and pancreatic cancer.

项目摘要/摘要 胰腺腺癌（PDAC）预计将是美国癌症死亡的第二大原因 2020年的总五年生存率<9％。早期转移是贫穷的主要原因之一 生存。最近比较原发性肿瘤和转移酶的基因组测序研究确定了相似的 存在突变，但没有发现特定的转移驱动因素。那是负责的机制 肿瘤进展，特别是用于转移的过程，需要进行更多研究。表观基因质调节和 上皮到间质转变（EMT）是肿瘤进展和 转移。我们发现miR455链接了转化生长因子-β（TGF-β）和EMT信号的链接 进行组蛋白修饰。 MiR455由TGF-β更新，这又减少了KMT2D的表达 KDM6A，两个组蛋白修饰酶。我们的数据还表明，MiR455或KDM6A的损失增加 表达促进了PDAC细胞EMT表型，迁移，侵袭，淋巴结转移和患者不良 生存。在此提案中，我们将定义MiR455介导的TGF-β信号与 PDAC进展和转移的表观遗传学修饰。我们的项目将揭示不良的 了解PDAC进展和转移中的表观遗传调节机制，这将进一步 有助于鉴定新的诊断和预后生物标志物和治疗靶标。 该应用程序的总体目标是为我提供更受保护的研究时间，获得初步数据和 表观遗传研究领域的出版，并为我发展新的关键技能，成为R01资助 表观遗传学和胰腺癌生物学的独立研究者。职业发展计划是基于的 关于正规课程，讲习班，讲座，会议，经验丰富的学习和指导的基础科学 训练。这个K08奖和额外的培训对我的职业发展至关重要，因为 在我的临床培训期间的科学差距，该领域的新知识和技术的发展以及 我目前的临床职责。我已经得到了部门的慷慨支持，并将与我的 主要导师，Yali Dou博士，博士，表观遗传学专家和同事Drs。 Mats Ljungman博士，A 转录法规和生物信息学领导者和玛丽娜·帕斯卡·迪·玛格丽亚诺（Marina Pasca Di Magliano） 胰腺癌领域和遗传小鼠模型生成和分析的专家。我也有 建立了一个咨询委员会，以进一步支持我作为成功的物理科学家的发展。我会 将至少75％的时间用于基础科学研究。密歇根大学和系 病理学在独立癌症研究人员的培训中具有杰出的历史。在一起， 该提案的要素将为我提供成为一个经验，培训和精神训练 在表观遗传学和胰腺癌领域成功独立的身体科学家。