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: 10459626
• 负责人: Roza Kamila Przanowska
• 金额: $ 9.5万
• 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/10459626
• 关键词: Accounting; Adult; Affect; Algorithms; Animal Model; Antineoplastic Agents; Antisense Oligonucleotides; Benign; Bioinformatics; Brain; Brain Neoplasms; Cancer Biology; Cancer Model; Cancer Prognosis; Cell physiology; Cells; Central Nervous System Neoplasms; Cessation of life; Chemicals; Chemotherapy and/or radiation; Classification; Clinical Trials; Combined Modality Therapy; Data; Diagnosis; Diagnostic; Disease; Disease remission; Drug Targeting; Epigenetic Process; Estrogen receptor positive; Evaluation; Excision; Exhibits; Exons; FDA approved; Focused Ultrasound; Future; Genes; Glioblastoma; Glioma; Gold; Grant; Heterogeneity; Histopathology; Immune response; Immune system; Immunotherapy; Knowledge; Lead; Location; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Methodology; Methods; MicroRNAs; Migration Assay; Mus; NF-kappa B; National Cancer Institute; Neoplasm Metastasis; Nervous system structure; Oncogenes; Oncogenic; Oncolytic viruses; Operative Surgical Procedures; Organism; Pathway interactions; Patients; Phase; Phosphotransferases; Postdoctoral Fellow; Prognosis; Proteins; Quality of life; RNA; RNA delivery; Radiation; Recurrence; Regulation; Regulatory Pathway; Research; Research Design; Research Personnel; Research Project Grants; Risk; Role; Scientist; Series; Signs and Symptoms; Specimen; Structure; Structure-Activity Relationship; Techniques; Testing; Therapeutic; Time; Training; Translating; Tumor Antibodies; Tumor Burden; Tumor Suppression; Tumor Suppressor Proteins; Untranslated RNA; Work; Xenograft procedure; base; bevacizumab; biomarker discovery; career; cell motility; chemotherapy; comparative; design; effective therapy; experimental study; improved; in vivo; malignant breast neoplasm; migration; mouse model; nanoparticle; non-oncogenic; novel; novel strategies; novel therapeutic intervention; overexpression; pre-doctoral; screening; targeted treatment; therapy development; tumor; tumor growth; tumor progression

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.

项目摘要/摘要 大约30％的脑肿瘤和中枢神经系统肿瘤是神经胶质瘤。他们也完成 所有恶性脑肿瘤的80％。神经胶质瘤是一种具有多种亚型的异质性疾病。这 根据谁进行神经病理学评估和脑肿瘤标本的诊断 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，可以根据其位置进行手术去除。 II级低 - gliomas（LGGS）倾向于暴露良性趋势，但它们的复发率也均匀 随着时间的推移，成绩增加。 III-IV级高级神经胶质瘤（包括胶质母细胞瘤； GBM）是恶性的，并且 带有最坏的预后。尽管进行了大量研究，但高级神经胶质瘤可能很难治疗 而且通常无法治愈。可用的多模式治疗，例如肿瘤惊喜，放射或化学疗法， TTF（肿瘤治疗），靶向药物治疗和免疫疗法，可能会减慢癌症的进展并减少 标志和符号以最大程度地提高患者的生活质量。尽管如此，患者的中位生存时间 高级神经胶质瘤仅为12-14个月。 在该项目的F99阶段，我提出了结构 - 两个参与的LNCRNA的功能研究 神经胶质瘤/GBM进展：致癌linc00152和抑制性肿瘤。工作的假设是 LNCRNA像蛋白质一样，具有特定的功能领域，负责其活动。调查 lncRNA结构与功能之间的关系，我建议确定（1） Linc00152和DRAIC使用形状映射技术和（2）Draic lncRNA域在该域中的功能 拟议的工作将 打开LNCRNA二级结构功能研究的新领域，该研究将允许更快的功能描述 与癌症相关的新型LNCRNA并定义了将来可以用于治疗的最小功能结构域。 同时，通过与这些领域专家的科学家互动，我将熟悉动物模型 和神经胶质瘤的组织病理学为K00工作阶段做准备。 在K00阶段，我将重点介绍如何靶向致癌性长和短的非编码RNA（NCRNA） 神经胶质瘤，并探索新的方法来传递肿瘤抑制剂NCRNA的最小功能结构域 用于神经胶质瘤治疗。我还将检查操纵非编码RNA结构如何影响生物的免疫 对RNA递送的响应。在F99阶段执行的工作以了解关键调节途径 受神经胶质瘤的LNCRNA的影响将使我在K00阶段可以设计目标的化学物质 这些途径，因此有助于开发新的治疗神经胶质瘤的方法。