The role of small RNA modifications in glioma

小RNA修饰在神经胶质瘤中的作用

• 批准号: 10371455
• 负责人: Zhangli Su
• 金额: $ 11.06万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-11 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371455
• 关键词: Address; Affect; Area; Base Pairing; Benchmarking; Biochemistry; Biogenesis; Bioinformatics; Biological Process; Biology; CRISPR screen; Cancer Biology; Cell Line; Cell Proliferation; Cells; Chemotherapy and/or radiation; Data; Data Set; Development; Disease Management; Ensure; Environment; Epigenetic Process; Family; Gene Expression; Gene Silencing; Genetic Transcription; Genomics; Glioblastoma; Glioma; Goals; Interruption; Investigation; Learning; Malignant Neoplasms; Malignant neoplasm of brain; Manuscripts; Mentors; MicroRNAs; Mining; Modification; Molecular Biology; Mus; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patients; Persons; Phase; Phenotype; Play; Positioning Attribute; Preparation; Primary Brain Neoplasms; Process; RNA; Recurrence; Regulation; Regulator Genes; Research; Role; Sampling; Shapes; Site; Small RNA; Techniques; Testing; The Cancer Genome Atlas; Training; Transfer RNA; Universities; Untranslated RNA; Virginia; Xenograft Model; Xenograft procedure; base; bioinformatics tool; cancer type; common treatment; effective therapy; experimental study; genomic tools; improved; in vivo; innovation; insight; mortality; new therapeutic target; novel; overexpression; prognostic; skills; stem-like cell; therapeutic target; tool; transcriptome; transcriptome sequencing; tumor

PROJECT SUMMARY/ABSTRACT Background: Small non-coding RNAs including microRNAs and tRNA-related fragments (tRFs) are important regulators of global gene expression and have been shown to play key roles in normal development. Recent evidence suggests small RNAs (especially tRFs) can be regulated via modifications, however global analysis of small RNA modifications in cancers is still lacking due to lack of tools. In this proposal I will test whether dysregulation of small RNA modifications play a role in cancer biology. I will focus on glioma/glioblastoma (GBM), vicious cancer types that are barely treatable. Research: The candidate's preliminary results indicate that tRFs are novel regulators of gene expression and cell phenotypes in gliomas and their activity could be regulated by small RNA modification status. The candidate already detected such small RNA modifications in GBM and GSC (glioma stem-like cells) cell lines and also GBM patients. This proposal aims to understand the biological functions of these newly identified small RNA modifications and tRFs in gliomas. If completed, this will bring novel insights to the field and be a perfect niche to launch an independent lab. Three aims are proposed, each based on preliminary data, and taking into the independent phase. Aim 1 will determine the glioma-relevant small RNA modification factors. Aim 2 will define the functional roles and targetome of glioma-prognostic tRFs. Aim 3 will elucidate novel RBP- based mechanisms of small RNA modification regulating tRF targetome and pathways in gliomas. GSC cultures and mouse xenografts, genomics and bioinformatics will be employed to tackle these questions. The proposed research plan will reveal a novel gene regulatory mechanism by small RNA modifications and identify potential therapeutic targets for glioma treatment. Candidate: The candidate's long-term goal is to utilize her background in biochemistry, small RNA and molecular biology to understand new gene regulatory mechanism in cancer biology. She already processes a lot of the skills needed to conduct proposed experiments, however she is in great need to obtain additional training in glioma biology in order to further test her hypothesis (with co-mentor who is an expert in GBM field). The K99 mentored phase will allow her to build on her current data, expand on several new areas, and learn new techniques to launch her own lab. A mentoring committee of 6 is proposed to ensure the candidate get guidance to help her achieve independence. Environment: The proposed project will be conducted at University of Virginia, which has an outstanding environment for the proposed training and research.

项目概要/摘要 背景：小非编码 RNA，包括 microRNA 和 tRNA 相关片段 (tRF) 很重要 全球基因表达的调节因子，并已被证明在正常发育中发挥关键作用。最近的 有证据表明小 RNA（尤其是 tRF）可以通过修饰进行调节，但总体分析 由于缺乏工具，目前仍缺乏对癌症中小 RNA 修饰的研究。在这个提案中我将测试是否 小 RNA 修饰的失调在癌症生物学中发挥着重要作用。我将重点关注神经胶质瘤/胶质母细胞瘤 （GBM），几乎无法治愈的恶性癌症类型。 研究：候选人的初步结果表明 tRF 是基因表达的新型调节因子 神经胶质瘤中的细胞表型及其活性可以通过小RNA修饰状态来调节。这 候选者已经在 GBM 和 GSC（神经胶质瘤干细胞样细胞）细胞系中检测到此类小 RNA 修饰 还有 GBM 患者。该提案旨在了解这些新发现的生物功能 神经胶质瘤中的小 RNA 修饰和 tRF。如果完成，这将为该领域带来新颖的见解，并成为 建立独立实验室的完美利基。提出了三个目标，每个目标都基于初步数据，以及 进入独立阶段。目标 1 将确定神经胶质瘤相关的小 RNA 修饰因子。 目标 2 将定义神经胶质瘤预后 tRF 的功能作用和靶标组。目标 3 将阐明新颖的 RBP- 基于小RNA修饰调节神经胶质瘤中tRF靶标组和通路的机制。 GSC 将利用培养物和小鼠异种移植物、基因组学和生物信息学来解决这些问题。这 拟议的研究计划将通过小RNA修饰揭示一种新的基因调控机制 确定神经胶质瘤治疗的潜在治疗靶点。 候选人：候选人的长期目标是利用她在生物化学、小RNA和 分子生物学了解癌症生物学中新的基因调控机制。她已经处理了一个 进行拟议实验所需的大量技能，但是她非常需要获得额外的技能 神经胶质瘤生物学培训，以进一步检验她的假设（与 GBM 领域的专家共同导师）。 K99 指导阶段将使她能够在当前数据的基础上扩展几个新领域，并学习 新技术来启动她自己的实验室。建议成立一个由 6 人组成的指导委员会，以确保候选人获得 指导帮助她实现独立。 环境：拟议的项目将在弗吉尼亚大学进行，该大学拥有出色的环境 拟议的培训和研究的环境。