Functional Analysis of LncRNAs in Epithelial Ovarian Cancer

上皮性卵巢癌中 LncRNA 的功能分析

• 批准号: 8679875
• 负责人: Kate Lawrenson
• 金额: $ 9.7万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8679875
• 关键词: American Association of Cancer Research; Animals; Apoptosis; Architecture; Award; BRCA1 gene; Bioinformatics; Biological Assay; Biological Markers; California; Cancer Center; Cancer Model; Cancer cell line; Candidate Disease Gene; Cataloging; Catalogs; Cell Culture Techniques; Cell Line; Cells; Clinic; Clinical; Clinical Sciences; Clinical Trials; Code; Collaborations; Communication; Complex; Comprehensive Cancer Center; Core Facility; DNA; Data; Data Analyses; Defect; Development; Diagnosis; Diagnostic; Disease; Educational workshop; Encyclopedia of DNA Elements; Environment; Epithelial Cells; Epithelial ovarian cancer; Equipment; Ethics; Exhibits; Faculty; Flow Cytometry; Focus Groups; Foundations; Functional RNA; Funding; Gene Expression Profile; Genes; Genetic; Genetic Research; Genome; Genome Components; Genomics; Goals; Grant; Health; Human; Human Genome; Hypermethylation; Image; In Vitro; Institutes; Institution; International; Intervention; Investigation; Joints; Journals; Laboratories; Lead; Length; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Massive Parallel Sequencing; Mentors; Mentorship; Modeling; Morbidity - disease rate; Mutate; Nature; Neoplasm Metastasis; Neoplasms; Normal Cell; Nucleotides; Outcome; Ovarian; Paper; Pathway interactions; Peer Review; Phase; Phenotype; Play; Positioning Attribute; Predisposition; Process; Prognostic Marker; Proteins; Proteome; Publishing; RNA Sequences; Recording of previous events; Research; Research Personnel; Resources; Role; Running; Scientist; Secretory Cell; Serous; Somatic Mutation; Specimen; Staging; Surface; Technology; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Intervention; Tissues; Training; Transcript; Translating; Translational Research; Translations; Travel; Tumor Suppressor Genes; USC/Norris Comprehensive Cancer Center and Hospital; United States; Universities; Woman; Work; Writing; anticancer research; base; cancer cell; cancer diagnosis; cancer initiation; cancer risk; cancer therapy; cancer type; career; career development; cell type; chemotherapy; clinically significant; disorder subtype; effective therapy; epigenome; functional genomics; homologous recombination; improved; in vivo; inhibitor/antagonist; insight; knock-down; member; mortality; new therapeutic target; next generation; next generation sequencing; novel; novel therapeutics; outcome forecast; overexpression; prognostic; programs; responsible research conduct; therapeutic target; three-dimensional modeling; transcriptomics; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Candidate. Dr Kate Lawrenson is a postdoctoral researcher at the University of Southern California who has developed a unique set of expertise in functional modeling of ovarian cancer development, and in the identification and characterization of long non-coding RNAs in ovarian cancer susceptibility. Through her graduate and postdoctoral studies Dr Lawrenson has established a productive track record in the ovarian cancer field, with 12 primary research papers published, five of which as first/joint-first author and one as last author. Her work has been published in high impact peer-reviewed journals including Nature Genetics, Nature Communications, Neoplasia and Laboratory Investigation. Dr Lawrenson's research has in part been funded by grants awarded to her by the Wright Foundation and the Ovarian Cancer Research Fund, and Dr Lawrenson has been awarded seven highly competitive travel awards, including three from the American Association for Cancer Research. Dr Lawrenson is an ideal candidate for a K99/R00 pathway to independence award. This award would enable her to achieve her goal of establishing an independent research group focusing on translational research into long non-coding RNAs (lncRNAs) lncRNAs as drivers of neoplasia and therapeutic targets for ovarian cancer. During the mentored phase Dr Lawrenson will work closely with her mentorship team to receive expert training in ovarian cancer modeling (from Dr S Gayther), lncRNA discovery and data analysis (from Dr TJ Triche), and clinical translation of the findings (from Dr D Tripathy). At the end of te K99 mentored phase Dr Lawrenson will apply for tenure-track research positions at USC or other institutions with exceptional ovarian cancer and/or genomics programs. Environment. USC is a nurturing, collaborative research environment in which talented early career scientists can genuinely thrive and develop independence. USC has a strong track history in analyses of the non protein- coding component of the genome: many of the group leaders at USC are part of large international consortia (such as TCGA, ROADMAP & ENCODE) and the environment at USC naturally promotes collaboration. The Faculty at USC place a strong emphasis on mentorship and career development, and within USC the Centre for Excellence in Research and the Clinical and Translational Science Institute have an established career development program, each semester hosting courses and workshops for formal training in grant writing, responsible conduct of research, management and ethics. Facilities and resources at USC are second to none. The Epigenome Core facility was the first dedicated epigenome centre in the US, and includes a world-class laboratory and extensive dedicated bioinformatics facilities. This core specializes in next-generation genomics approaches and will perform the RNA-sequencing aspects of this research. Additionally, the USC Norris Comprehensive Cancer Center (NCCC) is supported a NCI Canter Center Support Grant (P30CA014089). Within the NCCC is a wide range of core facilities, run by dedicated highly trained staff, that are available to all Cancer Centre members. Particularly relevant to this proposal are The Cell and Tissue Imaging Core, the Flow Cytometry core and the Small Animal Imaging core, all containing the newest state-of-the art equipment and analysis softwate. Research. Most cancer research to date has focused on the 2% of the genome that directly encodes proteins but recent advances in next-generation sequencing have enabled the detailed characterization of the non- protein coding genome. However, while projects such as the Encyclopedia of DNA Elements (ENCODE) have identified an abundance of DNA motifs and non-coding RNA species that regulate the human transcriptome and proteome, the relevance of these discoveries to cancer treatment and diagnosis remains largely unexplored. Long non-coding RNAs (lncRNAs) are transcripts over 200 nucleotides in length that are often differentially expressed in cancer. LncRNAs drive many key pathways in cancer cells and can regulate aggressive tumor phenotypes including metastasis, proliferation, apoptosis and invasion and so represent a host of novel opportunities for therapeutic intervention that have not yet been explored. This research aims to characterize lncRNAs in ovarian cancer and test the hypothesis that lncRNAs can be novel therapeutic targets for this disease. I will take three complementary approaches. Firstly I will characterize the function of lncRNAs I have identified as being differentially expressed during ovarian cancer development. Secondly I will test for synthetic lethal interactions between lncRNAs and BRCA1, a gene that is commonly mutated/downregulated in ovarian cancer. Thirdly I will use The Cancer Genome Atlas data to identify lncRNAs that are prognostic for ovarian cancer, and I will use unique three-dimensional models of ovarian cancer that I have developed to test the whether prognostic lncRNAs are involved in chemoreponse. Women with ovarian cancer have been treated with the same broad-acting, toxic chemotherapies since the 1970's, and new and more effective therapies are urgently needed. Ultimately, the results of this research could help to improve prognoses for the 22,000 women diagnosed with this disease annually in the United States.

描述（由申请人提供）：候选人。凯特·劳伦森（Kate Lawrenson）博士是南加州大学的博士后研究员，他在卵巢癌发展的功能建模以及卵巢癌敏感性中长期非编码RNA的鉴定和表征方面开发了独特的专业知识。通过她的研究生和博士后研究，劳伦森博士在卵巢癌领域建立了一项富有成效的往绩，并发表了12篇主要的研究论文，其中五篇是第一/联合第一作者，另一位是最后一位作者。她的工作已发表在高影响同行评审的期刊上，包括自然遗传学，自然传播，肿瘤和实验室调查。劳伦森博士的研究部分是由赖特基金会和卵巢癌研究基金授予她的赠款资助的，劳伦森博士获得了七项竞争激烈的旅行奖，其中包括美国癌症研究协会的三项。劳伦森博士是获得独立奖的K99/R00途径的理想候选人。该奖项将使她能够建立一个独立的研究小组，该小组专注于转化为长期非编码RNA（LNCRNA）LNCRNA作为肿瘤癌的驱动因素和卵巢癌的治疗靶标。在指导阶段，劳伦森博士将与她的指导团队紧密合作，以接受卵巢癌建模的专家培训（来自S Gayther博士），Lncrna Discovery和Data Analysis（来自TJ Triche博士）以及发现结果的临床翻译（来自Drichy博士）。在TE K99的指导阶段结束时，Lawrenson博士将在USC或其他具有特殊卵巢癌和/或基因组学计划的机构申请终身研究职位。环境。南加州大学是一种培养，合作的研究环境，有才华的早期职业科学家可以真正成长和发展独立性。 USC在分析基因组的非蛋白质编码成分的分析中具有很强的轨道历史：USC的许多小组领导者都是大型国际财团（例如TCGA，Roadmap＆Encode）的一部分，以及USC的环境自然促进了协作。南加州大学的教师非常重视指导和职业发展，在南加州大学，在USC研究中心和临床和转化科学学院的卓越中心都有一项既定的职业发展计划，每个学期举办课程和课程和讲习班，用于授予授予写作，负责任的研究，管理和伦理学的正式培训。南加州大学的设施和资源是首屈一指的。表观基因组核心设施是美国第一个专用的表观基因组中心，其中包括世界一流的实验室和广泛的专用生物信息学设施。该核心专门研究下一代基因组学方法，并将执行本研究的RNA测序方面。此外，USC Norris综合癌症中心（NCCC）得到了NCI CANTER CENTER支持拨款（P30CA014089）的支持。在NCCC内部是由专用训练有素的员工经营的各种核心设施，所有癌症中心成员都可以使用。与该建议特别相关的是细胞和组织成像核心，流式细胞仪芯和小动物成像核心，所有这些都包含最新的设备和分析软甘露。研究。迄今为止，大多数癌症研究都集中在直接编码蛋白质的基因组上的2％，但下一代测序的最新进展使得非蛋白质编码基因组的详细表征。但是，尽管诸如DNA元素百科全书（编码）之类的项目已经确定了调节人类转录组和蛋白质组的大量DNA基序和非编码RNA物种，但这些发现与癌症治疗和诊断的相关性仍然很大程度上尚未得到探索。长的非编码RNA（LNCRNA）是200多个核苷酸的转录本，通常在癌症中差异表达。 LNCRNA驱动癌细胞中的许多关键途径，并可以调节侵袭性肿瘤表型，包括转移，增殖，凋亡和入侵，因此代表了许多尚未探索治疗干预的新型机会。这项研究旨在表征卵巢癌中的LNCRNA，并检验LNCRNA可以成为该疾病的新型治疗靶点的假设。我将采用三种补充方法。首先，我将表征我确定为在卵巢癌发展过程中差异表达的LNCRNA的功能。其次，我将测试LNCRNA和BRCA1之间的合成致命相互作用，该基因通常在卵巢癌中突变/下调。第三，我将使用癌症基因组图集数据来识别卵巢癌预后的LNCRNA，并且我将使用我开发的独特的三维卵巢癌模型来测试预后lncrnas是否参与化学物质。自1970年代以来，患有卵巢癌的妇女已经接受了相同的广泛，有毒化学疗法的治疗，并且迫切需要新的，更有效的疗法。最终，这项研究的结果可能有助于改善美国每年在美国被诊断出患有这种疾病的22,000名妇女的预后。

项目成果

In vivo discovery of RNA proximal proteins via proximity-dependent biotinylation.

• DOI: 10.1080/15476286.2021.1917215
• 发表时间: 2021-12
• 期刊: RNA biology
• 影响因子: 4.1
• 作者: Lin X;Fonseca MAS;Breunig JJ;Corona RI;Lawrenson K
• 通讯作者: Lawrenson K

The PAX8 cistrome in epithelial ovarian cancer.

• DOI: 10.18632/oncotarget.22718
• 发表时间: 2017-12-12
• 期刊: Oncotarget
• 作者: Adler EK;Corona RI;Lee JM;Rodriguez-Malave N;Mhawech-Fauceglia P;Sowter H;Hazelett DJ;Lawrenson K;Gayther SA
• 通讯作者: Gayther SA