Long non-coding RNA Heterogeneity in ER + Breast Cancer

ER 乳腺癌中的长非编码 RNA 异质性

• 批准号: 10439933
• 负责人: Roza Kamila Przanowska
• 金额: $ 9.21万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439933
• 关键词: Long; non; coding; RNA; Heterogeneity

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.

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。 80% 的恶性脑肿瘤是一种具有多种亚型的异质性疾病。 根据WHO对脑肿瘤标本进行神经病理学评估和诊断 中枢神经系统肿瘤的分类：I级、II级、III级和IV级生物学良性。 神经胶质瘤的风险相对较低，可以根据其位置进行手术切除。 级别胶质瘤（LGG）往往表现出良性倾向，但它们也具有统一的复发率和 III-IV 级高级别胶质瘤（包括胶质母细胞瘤；GBM）是恶性的，并且随着时间的推移，级别会增加。 尽管进行了大量研究，但高级别神经胶质瘤的治疗仍然非常困难。 可用的多模式治疗，如肿瘤切除、放疗或化疗，通常无法治愈。 TTF（肿瘤治疗领域）、靶向药物治疗和免疫治疗，可能会减缓癌症进展并减少 体征和症状以最大限度地提高患者的生活质量仍然是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，我建议对涉及的两个lncRNA进行结构-功能研究 神经胶质瘤/GBM 进展：致癌 LINC00152 和肿瘤抑制 DRAIC 的工作假设是： lncRNA 与蛋白质一样，具有负责其活性的特定功能域。 lncRNA结构和功能之间的关系，我建议确定（1）的二级结构 使用 SHAPE-MaP 技术的 LINC00152 和 DRAIC 以及 (2) DRAIC lncRNA 结构域的功能 抑制迁移和侵袭以及抑制 NF-kB 通路的背景。 开辟了lncRNA二级结构-功能研究的新领域，这将允许更快地描述 新型癌症相关lncRNA，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科学家互动，我将熟悉动物模型 和神经胶质瘤的组织病理学，为 K00 阶段的工作做准备。 在K00阶段，我将重点关注如何靶向致癌的长短非编码RNA（ncRNA） 神经胶质瘤，并探索传递肿瘤抑制 ncRNA 最小功能域的新方法 对于神经胶质瘤治疗，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 递送的响应在 F99 阶段进行的工作，以了解关键的调控途径。 神经胶质瘤中 lncRNA 的影响将使我能够在 K00 阶段设计靶向化学物质的筛选 这些途径，从而有助于开发治疗神经胶质瘤的新方法。