Role of the Chromosome 19 MicroRNA Cluster in Liver Cancers

项目摘要 染色体19 microRNA簇（C19 MC）是基因组的调节部分，通常仅在 在胚胎发育和胎盘中。最近，布罗尔博士领导的工作表明， C19 MC的过度表达是一种罕见的未分化胚胎癌的基因组标志， 肝肉瘤[UESL]（Setty BA... Brohl AS，PLOS genetics，2020）。此外，他还表明，C19 MC 在最常见的成人癌症中，过表达是常见的，并且过表达与 重要的表型变化。在癌症类型中一致，例如在乳腺癌中（Jinesh GG... Brohl AS，PLOS One，2018）和肝细胞癌[HCC]（Jinesh GG... Brohl，AS，Scientific 报告，2020），C19 MC与未分化状态，干细胞样特征和治疗抗性有关。 在这项提案中，Brohl博士旨在进一步研究C19 MC在肝癌中的作用，包括 HCC和UESL。对罕见肿瘤和常见癌症中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提高 分离感兴趣的基因组特征的影响的能力、多样性和许多模型的可用性 常见癌症的系统将促进可复制性的研究和发现范围的评估。 重要的是，Brohl博士将产生新的模型，包括CRISP/Cas9敲低和C19 MC的诱导 这对科学界不仅对癌症生物学， 对C19 MC的研究感兴趣（例如胎盘研究）。 布罗尔博士完全有能力领导这项提案。他已经确立了自己作为一个临床专家， 罕见肿瘤患者的护理，具有强大的翻译基因组学研究记录，并已 主要负责支持这项工作的初步科学发现。他将主要 由艾尔莎弗洛雷斯博士指导，他是一位资金充足的资深科学家，在以下方面拥有丰富的经验和专业知识： 分子肿瘤学和非编码RNA生物学本提案的湿实验室部分将是 在她实验室的共享空间里进行，并有她的直接输入。该提案包括一个职业生涯 发展计划和研究计划，这将为Brohl博士提供必要的专业知识和数据， 他的目标是成为一名独立的科学家。除了弗洛雷斯博士，他的导师 顾问团队包括Damon Reed博士，他是一名高级临床和翻译研究员， 青少年和年轻成人癌症，和理查德金博士，临床研究人员和思想领袖， 肝细胞癌的治疗在完成本提案后，Brohl博士将处于有利地位， 向独立研究过渡。他计划在该奖项的倒数第二年提交R 01 根据这项工作产生的结果。

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.