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: 10840181
• 负责人: Zhangli Su
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10840181
• 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; Classification; Data; Data Set; Development; Disease Management; Ensure; Environment; Epigenetic Process; Family; Gene Expression; Gene Silencing; 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; posttranscriptional; 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.

项目摘要/摘要 背景：小型非编码RNA，包括microRNA和与TRNA相关的片段（TRF）很重要 全球基因表达的调节剂已被证明在正常发育中起关键作用。最近的 有证据表明，小型RNA（尤其是TRF）可以通过修改来调节，但是全球分析 由于缺乏工具，仍缺乏癌症中的小小的RNA修饰。在此提案中，我将测试是否 小RNA修饰的失调在癌症生物学中起作用。我将专注于神经胶质瘤/胶质母细胞瘤 （GBM），几乎无法治疗的恶性癌症类型。 研究：候选人的初步结果表明，TRF是基因表达和 神经胶质瘤中的细胞表型及其活性可以由小的RNA修饰状态调节。这 候选人已经在GBM和GSC（神经胶质瘤样细胞）细胞系中检测到了如此小的RNA修饰 还有GBM患者。该建议旨在了解这些新确定的生物学功能 胶质瘤中的小RNA修饰和TRF。如果完成，这将带来新颖的见解，并成为一个 完美的利基市场来启动独立实验室。提出了三个目标，每个目标都基于初步数据，并且 进入独立阶段。 AIM 1将确定与胶质瘤相关的小RNA修饰因子。 AIM 2将定义胶质瘤 - 原检测性TRF的功能作用和靶标。 AIM 3将阐明新颖的RBP- 基于小的RNA修饰的机制调节胶质瘤中的TRF靶标和途径。 GSC 将采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的RNA修饰揭示一种新型的基因调节机制和 确定胶质瘤治疗的潜在治疗靶标。 候选人：候选人的长期目标是利用她的背景在生物化学，小RNA和 了解癌症生物学中新基因调节机制的分子生物学。她已经处理了 进行拟议的实验所需的许多技能，但是她非常需要获得更多 为了进一步检验她的假设（与GBM领域的专家一起），在神经胶质瘤生物学上进行培训。 K99指导阶段将使她能够建立在当前的数据上，扩展几个新领域，并学习 推出自己的实验室的新技术。提出了一个由6人组成的指导委员会，以确保候选人获得 帮助她实现独立的指导。 环境：拟议的项目将在弗吉尼亚大学进行，该项目具有未杰出的 拟议培训和研究的环境。