Functional Analysis of LncRNAs in Epithelial Ovarian Cancer

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，在卵巢癌发展的功能建模以及卵巢癌易感性中长非编码RNA的鉴定和表征方面拥有独特的专业知识。通过她的研究生和博士后研究，Lawrenson博士在卵巢癌领域建立了富有成效的记录，发表了12篇主要研究论文，其中5篇是第一/联合第一作者，1篇是最后作者。她的工作已发表在高影响力的同行评审期刊上，包括Nature Genetics，Nature Communications，Neoplasia和Laboratory Investigation。Lawrenson博士的研究部分由Wright基金会和卵巢癌研究基金授予她的赠款资助，Lawrenson博士获得了七个极具竞争力的旅行奖，其中三个来自美国癌症研究协会。Lawrenson博士是K99/R 00独立奖的理想候选人。该奖项将使她能够实现建立一个独立研究小组的目标，该研究小组专注于将长非编码RNA（lncRNA）lncRNA转化为肿瘤形成和卵巢癌治疗靶点的驱动因素。在指导阶段，Lawrenson博士将与她的导师团队密切合作，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）以及临床翻译结果（来自D Tripathy博士）的专家培训。在K99指导阶段结束时，Lawrenson博士将申请南加州大学或其他具有特殊卵巢癌和/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，协作研究环境中，有才华的早期职业科学家可以真正茁壮成长，发展独立性。南加州大学在分析基因组的非蛋白质编码组分方面有着悠久的历史：南加州大学的许多小组领导人都是大型国际财团（如TCGA，ROADMAP和ENCODE）的一部分，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导师制和职业发展，在南加州大学内部，卓越研究中心和临床与转化科学研究所都有一个既定的职业发展计划，每学期举办课程和研讨会，用于资助写作，负责任的研究，管理和道德行为的正式培训。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门的表观基因组中心，包括一个世界级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。此外，南加州大学诺里斯综合癌症中心（NCCC）支持NCI坎特中心支持赠款（P30 CA 014089）。在NCCC内有一系列的核心设施，由训练有素的专业人员管理，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。Research.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详细表征非蛋白质编码基因组。然而，虽然DNA元件百科全书（ENCODE）等项目已经确定了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尚未探索。长非编码RNA（lncRNA）是长度超过200个核苷酸的转录物，其通常在癌症中差异表达。LncRNA驱动癌细胞中的许多关键途径，并且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的新机会。本研究旨在描述卵巢癌中lncRNA的特征，并验证lncRNA可以成为这种疾病的新治疗靶点的假设。我将采取三种相辅相成的办法。首先，我将描述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BRCA 1之间的合成致死相互作用，BRCA 1是一种在卵巢癌中通常突变/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有预后意义的lncRNA，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，患有卵巢癌的妇女一直接受相同的广谱毒性化疗，迫切需要新的更有效的治疗方法。最终，这项研究的结果可能有助于改善美国每年诊断患有这种疾病的22，000名妇女的健康状况。

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.