The role of small RNA modifications in glioma

项目总结/摘要 背景：小分子非编码RNA包括microRNA和tRNA相关片段（tRFs）是重要的 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 有证据表明，小RNA（尤其是tRF）可以通过修饰进行调节，但全球分析表明， 由于缺乏工具，癌症中的小RNA修饰仍然缺乏。在这份建议中，我将测试 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)几乎无法治愈的恶性癌症。 研究：候选人的初步结果表明，tRFs是基因表达的新型调节因子， 胶质瘤中的细胞表型及其活性可通过小RNA修饰状态调节。的 候选人已经在GBM和GSC（神经胶质瘤干细胞样细胞）细胞系中检测到这种小RNA修饰 以及GBM患者。这项建议旨在了解这些新发现的生物学功能， 胶质瘤中的小RNA修饰和tRF。如果完成，这将为该领域带来新的见解， 建立一个独立实验室的绝佳时机提出了三个目标，每个目标都基于初步数据， 进入独立阶段。目的1：确定胶质瘤相关的小RNA修饰因子。 目的2明确胶质瘤预后tRFs的功能作用和靶点。目的3将阐明新的RBP- 基于小RNA修饰调节tRF靶组和神经胶质瘤通路的机制。GSC 将采用细胞培养和小鼠异种移植、基因组学和生物信息学来解决这些问题。的 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， 鉴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，以了解癌症生物学中新的基因调控机制。她已经处理了一个 进行拟议的实验所需的技能很多，但她非常需要获得额外的 接受神经胶质瘤生物学培训，以进一步验证她的假设（与GBM领域的专家共同导师）。 K99辅导阶段将使她能够在现有数据的基础上，扩展几个新领域，并学习 新技术来建立她自己的实验室建议成立一个6人指导委员会，以确保候选人获得 帮助她实现独立。 环境：拟议的项目将在弗吉尼亚大学进行，该大学具有杰出的 为拟议的培训和研究提供环境。

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.