Functional Analysis of LncRNAs in Epithelial Ovarian Cancer

上皮性卵巢癌中 LncRNA 的功能分析

• 批准号: 9326937
• 负责人: Kate Lawrenson
• 金额: $ 22.74万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 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 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326937
• 关键词: American Association of Cancer Research; Apoptosis; Architecture; Award; BRCA1 gene; Bioinformatics; Biological Assay; California; Cancer Center; Cancer Model; Cancer cell line; Candidate Disease Gene; 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; Dimensions; Disease; Educational workshop; Encyclopedia of DNA Elements; Environment; Epithelial Cells; Epithelial ovarian cancer; Equipment; Ethics; Exhibits; Faculty; Flow Cytometry; Focus Groups; Foundations; Funding; Genes; Genetic; Genetic Research; Genome; Genome Components; Genomic approach; Genomics; Goals; Grant; Human; Human Genome; Hypermethylation; 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; Ovarian; Paper; Pathway interactions; Peer Review; Phase; Phenotype; Play; Positioning Attribute; Predisposition; Process; Prognostic Marker; Program Development; Proteins; Proteome; Publishing; Recording of previous events; Research; Research Personnel; Resources; Role; Running; Scientist; Secretory Cell; Serous; Somatic Mutation; Specimen; Surface; Susceptibility Gene; Talents; Technology; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Intervention; Tissue imaging; Tissues; Training; Transcript; Translational Research; Travel; Tumor Suppressor Genes; USC/Norris Comprehensive Cancer Center and Hospital; United States; Universities; Untranslated RNA; Woman; Work; Writing; animal imaging; anticancer research; base; cancer cell; cancer diagnosis; cancer initiation; cancer risk; cancer therapy; cancer type; career; career development; cell type; cellular imaging; chemotherapy; clinical biomarkers; clinical translation; clinically significant; diagnostic biomarker; differential expression; 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 prediction; overexpression; prognostic; programs; public health relevance; responsible research conduct; tenure track; therapeutic target; three-dimensional modeling; transcriptome; transcriptome sequencing; 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。 Kate Lawrenson 博士是南加州大学的博士后研究员，她在卵巢癌发展的功能模型以及卵巢癌易感性中长非编码 RNA 的识别和表征方面拥有一套独特的专业知识。通过研究生和博士后研究，Lawrenson 博士在卵巢癌领域建立了卓有成效的记录，发表了 12 篇主要研究论文，其中 5 篇为第一/共同第一作者，1 篇为最后作者。她的研究成果发表在高影响力的同行评审期刊上，包括《自然遗传学》、《自然通讯》、《肿瘤》和《实验室调查》。劳伦森博士的研究部分由赖特基金会和卵巢癌研究基金会授予的资助资助，劳伦森博士曾获得七项竞争激烈的旅行奖，其中三项来自美国癌症研究协会。 Lawrenson 博士是获得 K99/R00 独立途径奖的理想候选人。该奖项将使她能够实现建立一个独立研究小组的目标，专注于长非编码 RNA (lncRNA) 的转化研究，lncRNA 作为肿瘤形成的驱动因素和卵巢癌的治疗靶点。在指导阶段，Lawrenson 博士将与其指导团队密切合作，接受卵巢癌建模（来自 S Gayther 博士）、lncRNA 发现和数据分析（来自 TJ Triche 博士）以及研究结果的临床转化（来自 D Tripathy 博士）方面的专家培训。在 K99 指导阶段结束时，劳伦森博士将申请南加州大学或其他拥有特殊卵巢癌和/或基因组学项目的机构的终身研究职位。环境。南加州大学是一个培育、协作的研究环境，有才华的早期职业科学家可以在其中真正茁壮成长并发展独立性。南加州大学在基因组非蛋白质编码成分分析方面拥有悠久的历史：南加州大学的许多小组领导者都是大型国际联盟（例如 TCGA、ROADMAP 和 ENCODE）的成员，南加州大学的环境自然促进了合作。南加州大学的教师非常重视指导和职业发展，南加州大学卓越研究中心和临床与转化科学研究所拥有既定的职业发展计划，每学期都会举办拨款写作、负责任的研究行为、管理和道德方面的正式培训课程和研讨会。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门的表观基因组中心，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，并将执行这项研究的 RNA 测序方面的工作。此外，南加州大学诺里斯综合癌症中心 (NCCC) 还获得 NCI Canter 中心支持补助金 (P30CA014089) 的支持。 NCCC 内拥有各种核心设施，由训练有素的专业工作人员运营，可供所有癌症中心成员使用。与该提案特别相关的是细胞和组织成像核心、流式细胞术核心和小动物成像核心，所有这些都包含最新的最先进的设备和分析软件。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的 2% 上，但下一代测序的最新进展已经能够对非蛋白质编码基因组进行详细表征。然而，虽然 DNA 元素百科全书 (ENCODE) 等项目已经鉴定出大量调节人类转录组和蛋白质组的 DNA 基序和非编码 RNA 种类，但这些发现与癌症治疗和诊断的相关性在很大程度上仍未得到探索。长非编码 RNA (lncRNA) 是长度超过 200 个核苷酸的转录物，通常在癌症中差异表达。 LncRNA 驱动癌细胞中的许多关键通路，并可以调节侵袭性肿瘤表型，包括转移、增殖、凋亡和侵袭，因此代表了许多尚未探索的治疗干预新机会。本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治疗靶点的假设。我将采取三种互补的方法。首先，我将描述我已确定的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 之间的合成致死相互作用，BRCA1 是卵巢癌中常见突变/下调的基因。第三，我将使用癌症基因组图谱数据来识别对卵巢癌具有预后作用的lncRNA，并且我将使用我开发的独特的卵巢癌三维模型来测试预后lncRNA是否参与化学反应。自 20 世纪 70 年代以来，患有卵巢癌的女性一直接受相同的广效、有毒的化疗方法，因此迫切需要新的、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诊断出患有这种疾病的 22,000 名女性的预后。