Role of the Chromosome 19 MicroRNA Cluster in Liver Cancers

19 号染色体 MicroRNA 簇在肝癌中的作用

• 批准号: 10468875
• 负责人: Andrew Scott Brohl
• 金额: $ 24.88万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-12 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468875
• 关键词: Adolescent and Young Adult; Adult; Advisory Committees; Affect; Area; Award; Biological Models; Biology; Breast Sarcoma; CRISPR/Cas technology; Cancer Biology; Cells; Chromosomal translocation; Chromosome 19; Clinic; Clinical; Communities; Data; Development; Development Plans; Embryo; Evaluation; Foundations; Funding; Future; Genetic; Genetic study; Genome; Genomics; Goals; Hepatic Sarcoma; Human; In Vitro; Individual; Laboratories; Lead; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of liver; Mentors; Mentorship; MicroRNAs; Modeling; Molecular; Molecular Analysis; Molecular Genetics; Molecular Profiling; Neoplasm Metastasis; Normal tissue morphology; Oncogenic; Patient Care; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physicians; Physiology; Placenta; Positioning Attribute; Primary carcinoma of the liver cells; Program Development; Property; Proteomics; Regulation; Reporting; Research; Research Design; Research Personnel; Resistance; Role; Scientist; Senior Scientist; Signal Transduction; Specialist; Structure; Study models; Surveys; System; The Cancer Genome Atlas; Therapeutic; Therapeutic Intervention; Thinking; Translational Research; Undifferentiated; Untranslated RNA; Up-Regulation; Work; Xenograft Model; base; cancer type; career; career development; chemotherapy; clinical development; clinical effect; exceptional responders; experience; hepatocellular carcinoma cell line; in silico; in vivo; insight; interest; knock-down; laboratory experience; malignant breast neoplasm; metaplastic cell transformation; miRNA expression profiling; migration; molecular oncology; neoplastic cell; novel; overexpression; predictive marker; programs; rare cancer; research and development; response; standard of care; stem; stem-like cell; synergism; targeted treatment; therapy resistant; transcriptome sequencing; translational genomics; translational scientist; tumor; tumorigenesis; tumorigenic

Project Summary The chromosomal 19 microRNA cluster (C19MC) is a regulatory part of the genome normally only active during embryological development and in the placenta. Recently, Dr. Brohl has led work showing that extreme overexpression of C19MC is a genomic hallmark of a rare cancer, undifferentiated embryonic sarcoma of the liver [UESL] (Setty BA… Brohl AS, PLOS genetics, 2020). Further, he has shown that C19MC overexpression is frequent amongst most common adult cancers and that overexpression is linked to important phenotypic changes. Consistently across cancer types, for example in breast cancer (Jinesh GG…Brohl AS, PLOS One, 2018) and hepatocellular carcinoma [HCC] (Jinesh GG…Brohl, AS, Scientific Reports, 2020), C19MC is linked to an undifferentiated status, stem-like features, and therapy resistance. In this proposal, Dr. Brohl aims to further investigate the role of C19MC in liver cancers, including both HCC and UESL. In parallel study of the same molecular feature in both a rare tumor and common cancer will allow him to utilize the advantages of both: genomic and phenotypic uniformity of the rare cancer will enhance the ability to isolate the effects of the genomic feature of interest, diversity and availability of numerous model systems of the common cancer will facilitate study of replicability and evaluation of the scope of findings. Importantly, Dr. Brohl will generate new models, including CRISP/Cas9 knockdown and induction of C19MC expression that will be valuable for the scientific community not only for cancer biology but for anyone interested in the study of C19MC (e.g. placental research). Dr. Brohl is well positioned to lead this proposal. He has already established himself as a clinical expert in the care of patients with rare tumors, has a robust record of translational genomics research, and has been principally responsible for the preliminary scientific findings supporting this work. He will be primarily mentored by Dr. Elsa Flores, a well-funded senior scientist who has substantial experience and expertise in molecular oncology and non-coding RNA biology. The wet-laboratory component of this proposal will be conducted in shared space from her lab and with her direct input. The proposal includes a career development plan and research plan that will provide Dr. Brohl with the expertise and data necessary to reach his goal of becoming an independent physician-scientist. In addition to Dr. Flores, his mentorship and advisory team includes Dr. Damon Reed, a senior clinical and translational researcher with expertise in adolescent and young adult cancers, and Dr. Richard Kim, a clinical researcher and thought leader in the treatment of hepatocellular carcinoma. Upon completion of this proposal, Dr. Brohl will be well positioned to transition to research independence. He plans to submit an R01 during the penultimate year of this award based on the results generated from this work.

项目摘要 染色体19微核糖核酸簇(C19MC)是基因组的一个调节部分，通常只有活性 在胚胎发育和胎盘中。最近，布罗尔博士领导的研究表明， C19MC的过度表达是一种罕见的未分化胚胎癌的基因组特征 肝脏肉瘤(Setty BA…Brohl As，《公共科学图书馆遗传学》，2020)。此外，他还证明了C19MC 在大多数常见的成人癌症中，过度表达是常见的，这种过度表达与 重要的表型变化。在癌症类型之间保持一致，例如乳腺癌(JINESH GG…Brohl AS，PLOS One，2018年)和肝细胞癌(JINESH GG…Brohl，AS，Science 报告，2020)，C19MC与未分化状态、干细胞样特征和治疗耐药有关。 在这项提案中，Brohl博士的目标是进一步研究C19MC在肝癌中的作用，包括 肝细胞癌和UESL。在一种罕见肿瘤和常见癌症中对相同分子特征的平行研究将 允许他利用两者的优势：罕见癌症的基因组和表型一致性将增强 分离感兴趣的基因组特征的影响的能力、多样性和众多模型的可用性 常见癌症的系统将促进对可复制性的研究和对发现范围的评估。 重要的是，Brohl博士将产生新的模型，包括CRISP/Cas9基因敲除和C19MC的诱导 不仅对癌症生物学，而且对任何人都有价值的表达 对C19MC的研究感兴趣(例如胎盘研究)。 布罗尔博士处于领导这项提议的有利地位。他已经确立了自己作为临床专家的地位。 对罕见肿瘤患者的护理，在翻译基因组学研究方面有着良好的记录，并一直 主要负责支持这项工作的初步科学发现。他将主要是 由Elsa Flores博士指导，Elsa Flores博士是一位资金雄厚的资深科学家，在 分子肿瘤学和非编码RNA生物学。这项提案的湿实验室部分将是 在她的实验室和她的直接输入的共享空间中进行。这份提案包括一份职业 开发计划和研究计划，将为Brohl博士提供必要的专业知识和数据 实现了他成为一名独立内科科学家的目标。除了弗洛雷斯博士，他的导师 咨询团队包括达蒙·里德博士，他是一名高级临床和翻译研究员，在 青少年和青壮年癌症，以及理查德·金博士，临床研究员和思想领袖 肝细胞癌的治疗。在完成这项提议后，Brohl博士将很好地 向研究独立过渡。他计划在该奖项的倒数第二年提交R01 根据这项工作产生的结果。