Long non-coding RNA Heterogeneity in ER + Breast Cancer

项目摘要/摘要 大约30%的脑瘤和中枢神经系统肿瘤是胶质瘤。它们还包括 占所有恶性脑瘤的80%。胶质瘤是一种具有多种亚型的异质性疾病。这个 根据世界卫生组织的要求，对脑肿瘤标本进行神经病理学评估和诊断 中枢神经系统肿瘤分类：I级、II级、III级和IV级。I级生物良性 神经胶质瘤的风险相对较低，可以根据其位置进行手术切除。二级低- 级别胶质瘤(LGG)倾向于表现为良性，但它们的复发率和 随着时间的推移，分数会增加。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。尽管进行了大量研究，但高级别胶质瘤可能很难治疗。 而且大多数情况下是无法治愈的。可用的多种治疗方法，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，可能会减缓癌症的进展和减少 以最大限度地提高患者的生活质量。尽管如此，慢性阻塞性肺疾病患者的中位生存时间 高级别胶质瘤只有12-14个月。 在这个项目的F99阶段，我提议对参与其中的两个lncRNAs进行结构-功能研究 胶质瘤/基底膜进展：致癌基因LINC00152和肿瘤抑制基因。工作假说是 与蛋白质一样，lncRNAs也有负责其活动的特定功能域。为了调查 LncRNA结构与功能的关系，我建议确定(1)LncRNA的二级结构 LINC00152和DRAIC使用SHAPE-MAP技术和(2)DRAIC LncRNA结构域的功能 抑制迁移和侵袭以及抑制核因子-kB途径。拟议的工作将 开辟了LncRNA二级结构-功能研究的新领域，从而可以更快地描述LncRNA的功能 新的与癌症相关的lncRNAs，并定义了未来可用于治疗的最小功能域。 同时，通过与这些领域的专家进行互动，我将熟悉动物模型 以及胶质瘤的组织病理学，为K00阶段的工作做准备。 在K00阶段，我将重点介绍如何针对致癌的长和短非编码RNA(NcRNAs) 并探索传递肿瘤抑制基因ncRNAs最小功能结构域的新方法 用于神经胶质瘤的治疗。我还将研究操纵非编码RNA结构如何影响生物体的免疫 对RNA传递的响应。在F99阶段完成的了解关键调控途径的工作 在胶质瘤中受到lncRNA的影响将使我在K00阶段为将靶向的化学物质设计筛选 这些途径，并因此有助于开发治疗胶质瘤的新方法。

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.