Functional Analysis of LncRNAs in Epithelial Ovarian Cancer

描述(申请人提供)：候选人。凯特·劳伦森博士是南加州大学的博士后研究员，她在卵巢癌发生的功能建模以及卵巢癌易感性中长非编码RNA的识别和特征方面开发了一套独特的专业知识。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卓有成效的记录，发表了12篇主要研究论文，其中5篇是第一作者/联合第一作者，1篇是最后作者。她的研究成果已发表在包括《自然遗传学》、《自然通讯》、《新生疾病》和《实验室调查》在内的高影响力同行评议期刊上。劳伦森博士的研究部分资金来自莱特基金会和卵巢癌研究基金授予她的拨款，劳伦森博士已经获得了七个竞争激烈的旅行奖项，其中三个来自美国癌症研究协会。劳伦森博士是K99/R00独立之路奖的理想候选人。这一奖项将使她能够实现她的目标，即建立一个独立的研究小组，专注于将长非编码RNA(LncRNAs)作为肿瘤发生的驱动因素和卵巢癌治疗靶点的翻译研究。在指导阶段，劳伦森博士将与她的指导团队密切合作，接受卵巢癌建模(来自S·盖瑟博士)、lncRNA发现和数据分析(来自TJ Triche博士)以及研究结果的临床翻译(来自D·特里帕西博士)方面的专家培训。在TE 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教职研究职位。环境南加州大学是一个培育、协作的研究环境，在这个环境中，有才华的早期职业科学家可以真正茁壮成长并发展独立性。南加州大学在分析基因组的非蛋白质编码部分方面有着良好的历史：南加州大学的许多小组负责人都是大型国际财团(如TCGA、路线图和ENCODE)的成员，南加州大学的环境自然促进了合作。南加州大学的学院非常重视导师指导和职业发展，在南加州大学内，卓越研究中心和临床与翻译科学研究所都有既定的职业发展计划，每学期都会举办课程和研讨会，以进行拨款撰写、负责任的研究、管理和伦理方面的正式培训。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。这个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)得到了NCI坎特中心支持赠款(P30CA014089)的支持。在NCCC内有一系列的核心设施，由训练有素的敬业工作人员运营，所有癌症中心成员都可以使用。与这项提议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，所有这些核心都包含最新的最先进的设备和分析软件。研究。到目前为止，大多数癌症研究都集中在直接编码蛋白质的2%的基因组上，但新一代测序的最新进展使非蛋白质编码基因组的详细特征成为可能。然而，尽管诸如DNA元素百科全书(ENCODE)这样的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物种，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(LncRNAs)是长度超过200个核苷酸的转录本，通常在癌症中差异表达。LncRNAs在癌细胞中驱动许多关键途径，并能调节肿瘤的侵袭性表型，包括转移、增殖、凋亡和侵袭，因此为治疗干预提供了许多尚未被探索的新机会。本研究旨在鉴定卵巢癌中的lncRNAs，并验证lncRNAs可作为卵巢癌新的治疗靶点的假说。我将采取三种相辅相成的方法。首先，我将描述在卵巢癌发生过程中差异表达的lncRNAs的功能。其次，我将测试lncRNAs和BRCA1之间的合成致命相互作用，BRCA1是卵巢癌中常见的突变/下调基因。第三，我将使用癌症基因组图谱数据来识别对卵巢癌预后有影响的lncRNAs，并将使用我开发的独特的卵巢癌三维模型来测试预后lncRNAs是否参与了化学反应。自20世纪70年代S以来，卵巢癌患者一直接受同样的广效、毒性的化疗，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被诊断患有这种疾病的2.2万名女性的预后。

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.