Long non-coding RNA Heterogeneity in ER + Breast Cancer

项目概要/摘要 大约30%的脑肿瘤和中枢神经系统肿瘤是神经胶质瘤。它们还包括 百分之八十的恶性脑肿瘤神经胶质瘤是一种异质性疾病，具有多种亚型。的 脑肿瘤标本的神经病理学评价和诊断根据WHO 中枢神经系统肿瘤的分类：I、II、III和IV级。I级生物学良性 神经胶质瘤的风险相对较低，可以根据其位置通过手术切除。二级低- 级别胶质瘤（LGG）往往表现出良性倾向，但它们也有统一的复发率， 随着时间的推移而增加。III-IV级高级别胶质瘤（包括胶质母细胞瘤; GBM）是恶性的， 预后最差。尽管有大量的研究，高级别胶质瘤可能非常难以治疗 而且大多数情况下没有疗效。现有的多模式治疗，如肿瘤切除、放疗或化疗， TTF（肿瘤治疗领域），靶向药物治疗和免疫治疗，可以减缓癌症进展， 以最大限度地提高患者的生活质量。尽管如此，患者的中位生存时间 高级别胶质瘤仅需12-14个月。 在这个项目的F99阶段，我提出了两个lncRNA的结构-功能研究， 胶质瘤/GBM进展：致癌LINC 00152和肿瘤抑制性DRAIC。工作假设是， 与蛋白质一样，lncRNA具有负责其活性的特定功能结构域。探讨 lncRNA的结构和功能之间的关系，我建议确定（1）的二级结构 （2）使用SHAPE-MaP技术对LINC 00152和DRAIC中DRAIC lncRNA结构域的功能进行分析; 在抑制迁移和侵袭以及抑制NF-κ B途径的背景下。拟议的工作将 开启了lncRNA二级结构-功能研究的新领域，这将允许更快地描述lncRNA的功能。 新的癌症相关的lncRNA，并确定最小的功能域，可用于在未来的治疗。 同时，通过与这些领域的专家进行交流，我将熟悉动物模型 和神经胶质瘤的组织病理学，为K 00阶段的工作做准备。 在K 00阶段，我将专注于如何靶向致癌的长和短非编码RNA（ncRNA）， 神经胶质瘤，并探索新的方法来提供肿瘤抑制ncRNAs的最小功能域 神经胶质瘤治疗我还将研究如何操纵非编码RNA结构影响生物体的免疫 对RNA递送的反应。在F99阶段进行的工作，以了解关键的监管途径 在神经胶质瘤中受到lncRNA的影响，将使我在K 00阶段设计化学物质的筛选， 这些途径，从而有助于开发治疗神经胶质瘤的新方法。

Project Summary/Abstract About 30 percent of all brain tumors and central nervous system tumors are gliomas. They also comprise 80 percent of all malignant brain tumors. Glioma is a heterogeneous disease with multiple subtypes. The neuropathological evaluation and diagnostics of brain tumor specimens are performed according to WHO Classification of Tumors of the Central Nervous System: grades I, II, III and IV. Grade I biologically benign gliomas are comparatively low risk and can be removed surgically depending on their location. Grade II low- grade gliomas (LGGs) tend to exhibit benign tendencies, but they also have a uniform rate of recurrence and increase in grade over time. Grade III-IV high-grade gliomas (including glioblastoma; GBM) are malignant and carry the worst prognosis. Despite vast amounts of research, high-grade gliomas can be very difficult to treat and most often not curative. The multimodal treatments available, like tumor excision, radiation or chemotherapy, TTF (tumor treating fields), targeted drug therapy and immunotherapy, may slow cancer progression and reduce signs and symptoms in order to maximize a patient’s quality of life. Still, the median survival time of patients with high-grade gliomas is only 12–14 months. In the F99 phase of this project, I propose structure – function studies of two lncRNAs involved in glioma/GBM progression: oncogenic LINC00152 and tumor suppressive DRAIC. The working hypothesis is that lncRNAs, like proteins, have specific functional domains responsible for their activities. To investigate the relationship between lncRNA structure and function, I propose to determine (1) the secondary structure of LINC00152 and DRAIC using SHAPE-MaP technique and (2) the functionality of DRAIC lncRNA domains in the context of suppression of migration and invasion, and inhibition of the NF-kB pathway. The proposed work will open a new field of lncRNA secondary structure-function studies, which will allow faster functional description of novel cancer-related lncRNAs and define minimal functional domains that can be used in the future for therapy. In parallel, by interacting with scientists who are experts in those fields, I will familiarize myself with animal models and histopathology of gliomas to prepare for the K00 phase of work. In the K00 phase, I will focus on how to target oncogenic long and short non-coding RNAs (ncRNAs) in gliomas, and explore novel methods to deliver the minimal functional domains of the tumor suppressor ncRNAs for glioma therapy. I will also examine how manipulating noncoding RNA structure affects an organism’s immune response to the RNA delivery. Work performed in the F99 phase to understand key regulatory pathways impacted by lncRNAs in gliomas will allow me in the K00 phase to design screens for chemicals that will target these pathways, and thus help to develop novel approaches for treating gliomas.