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Impact of Tat-binding Cellular LncRNAs on HIV replication

Tat 结合细胞 LncRNA 对 HIV 复制的影响

基本信息

批准号：
9763448
负责人：
Smita Kulkarni
金额：
$ 23.94万
依托单位：
TEXAS BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-16 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763448
关键词：
Address Affect Anti-HIV Therapy Antisense RNA Binding Binding Proteins CD4 Positive T Lymphocytes Cell Line Cell physiology Cells Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Data Development Disease Disease Outcome Gene Expression Gene Expression Regulation Genetic Transcription HIV HIV Infections HIV tat Protein Host Defense Human Immune System Diseases Immune response Immunoprecipitation In Vitro Investigation MALAT1 gene Mediating MicroRNAs Modeling Molecular Molecular Target Outcome Study Pathogenesis Positioning Attribute Process Proteins RNA RNA Decay RNA Splicing Reporting Repression Retroviridae Role Techniques Transactivation Transcript Translations Untranslated RNA Viral Viral Proteins Virus Diseases Virus Replication crosslink crosslinking and immunoprecipitation sequencing diagnostic biomarker experience experimental study gag Gene Products in vitro Model insight loss of function novel particle protein degradation protein expression therapeutic target trafficking transcriptome

项目摘要

Summary Non-coding RNAs (ncRNA) represent the majority of the human transcriptome. The long non-coding RNAs (LncRNA) regulate a myriad of cellular, developmental, immune response and disease-associated processes and are emerging as diagnostic biomarkers. Recent reports have demonstrated the importance of cellular LncRNAs on HIV replication and latency. LncRNAs interact with HIV proteins but the precise roles of these interactions in viral replication, latency, and reactivation are largely unknown. LncRNAs have been shown to swiftly and efficiently regulate cellular trafficking, localization, and function of their protein binding partners. LncRNAs are modulated upon viral infection, thus they can rapidly interact with viral proteins and influence viral replication cycle in the cells. However, the possibility that the cellular LncRNAs interact with viral proteins directly to enhance or interfere with their function and affect viral replication has not been explored systematically. The HIV-Tat protein is known to interact with cellular RNAs and at least one LncRNA, NRON. In our preliminary investigation, we found 20 novel interactions between Tat and cellular LncRNAs. One of the Tat binding LncRNAs, metastasis associated lung adenocarcinoma transcript 1 (MALAT1) inhibited HIV replication in a cell line model as well as ex vivo infected primary CD4+ T cells. We hypothesize that MALAT1 influences HIV infection through its interaction with Tat. In this proposal, we seek to develop a Clustered Regularly Interspaced Short Palindromic Repeats interference (CRISPRi) loss-of-function screen and determine the effects of top 5 Tat-binding cellular LncRNAs on HIV replication (Aim1) and molecular mechanisms of MALAT1 mediated HIV inhibition (Aim2). The proposed study will be the first to comprehensively dissect the impact of Tat binding cellular LncRNAs on HIV. The LncRNAs found to affect HIV replication can be used as potential therapeutic targets. The data generated will expand the current information on the role of cellular LncRNAs in HIV infection, discover functionally relevant novel interactions between LncRNAs and HIV proteins and identify molecular targets for anti-HIV therapy.

总结非编码RNA（ncRNA）代表了人类转录组的大部分。长链非编码RNA LncRNA调节无数的细胞、发育、免疫应答和疾病相关过程并且正在成为诊断生物标志物。最近的报告表明， LncRNA对HIV复制和潜伏期的影响LncRNA与HIV蛋白相互作用，但这些蛋白的确切作用病毒复制、潜伏期和再活化中的相互作用在很大程度上是未知的。已显示lncRNA 快速和有效地调节细胞运输、定位和它们蛋白质结合配偶体的功能。 LncRNA在病毒感染时受到调节，因此它们可以快速与病毒蛋白相互作用并影响病毒的表达。细胞中的复制周期。然而，细胞LncRNA与病毒蛋白直接相互作用的可能性是未知的。增强或干扰它们的功能并影响病毒复制的作用尚未系统地研究。的已知HIV-Tat蛋白与细胞RNA和至少一种LncRNA（NRON）相互作用。在我们的初步调查中通过研究，我们发现了20种新的达特与细胞LncRNA之间的相互作用。其中一个达特装订 LncRNA，转移相关肺腺癌转录本1（MALAT 1）抑制HIV在细胞中的复制系模型以及离体感染的原代CD 4 + T细胞。我们假设MALAT 1影响HIV 通过与达特相互作用感染。在这项建议中，我们寻求发展一个有规律间隔的短回文重复干扰（CRISPRi）功能丧失筛选并确定前5名的影响 Tat结合细胞LncRNA对HIV复制的影响（Aim 1）及MALAT 1介导HIV的分子机制抑制（Aim 2）。这项拟议的研究将是第一个全面剖析达特结合细胞的影响， LncRNA对HIV的影响。发现影响HIV复制的LncRNA可以用作潜在的治疗靶点。所产生的数据将扩大目前关于细胞LncRNA在HIV感染中的作用的信息，发现 LncRNA和HIV蛋白之间的功能相关的新的相互作用，并确定分子靶点，抗艾滋病治疗