Control of HIV-1 Transcription by CPSF6 and PP2A
CPSF6 和 PP2A 对 HIV-1 转录的控制
基本信息
- 批准号:10693519
- 负责人:
- 金额:$ 23.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-07 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:BiologyCDK9 Protein KinaseCellsCleavage And Polyadenylation Specificity FactorComplexDNA Polymerase IIEffectivenessFDA approvedGene ExpressionGenetic TranscriptionHIVHIV-1ImmuneIn VitroInfectionInvestigationMediatingMethodsMinorityMolecularOutputPersonsPhosphoric Monoester HydrolasesPhosphorylationProtein DephosphorylationProtein Phosphatase InhibitorProtein phosphataseProteinsProteolysisProteomicsProvirusesRNARegulationT-LymphocyteTestingTherapeutic AgentsTranscriptional RegulationViralVirus Latencycancer typedesignexperimental studyin vivoinnovationnovelnovel strategiesnovel therapeutic interventionnovel therapeuticspharmacologicpromoterreactivation from latencytoolubiquitin ligaseubiquitin-protein ligase
项目摘要
PROJECT SUMMARY
The major barrier toward the eradication of HIV-1 infection is the presence of a small reservoir of latently
infected cells that escape immune-mediated clearance. Due to the lack of transcriptional activity, latent
proviruses in vivo are not easily detectable and cannot be targeted by either natural immune mechanisms or
molecular therapies. Therefore, understanding how HIV-1 transcription is regulated will open doors to novel
therapeutic strategies targeting the latent reservoir.
Pharmacological approaches to reactivate the latent reservoir in vivo have been considered as potential
eradication therapies for more than a decade. However, the effectiveness of these approaches has been
disappointing as only a minority of latently infected cells appear to be responsive to latency-reversing agents. A
deeper understanding of the transcriptional regulation of the HIV-1 promoter is necessary before we can design
novel and effective LRAs. Cleavage and polyadenylation specificity factor 6 (CPSF6) is a cellular protein with
multiple functions both in cellular and viral biology. Our recent finding that CPSF6 controls the stability and activity
of PP2A, a phosphatase directly implicated in the de-phosphorylation and inactivation of CDK9 and RNA Pol II,
reveals an exciting new line of investigation into potential cure strategies. This proposal will focus on the following
innovative directions: (a) to further understand the factors regulating HIV-1 transcription, with a focus on CPSF6
and PP2A; (b) to explore the possibility of using PP2A inhibition as a method to reactivate latent viruses; and (3)
to further explore the unknown functions of CPSF6 based on a recent proteomics experiment from our group
yielding several exciting hits.
项目摘要
根除HIV-1感染的主要障碍是存在一个小的潜伏性HIV-1感染的储存库。
感染的细胞逃避免疫介导的清除。由于缺乏转录活性,潜在的
体内的前病毒不容易被检测到,并且不能被天然免疫机制或
分子疗法因此,了解HIV-1转录是如何调节的将为新的研究打开大门。
针对潜在储库的治疗策略。
药理学方法,以重新激活潜在的水库在体内已被认为是潜在的
根除疗法已经有十多年了然而,这些方法的有效性一直受到
这是令人失望的,因为只有少数潜伏感染的细胞似乎对潜伏逆转剂有反应。一
在我们设计一个新的HIV-1启动子之前,
新的和有效的LRA。裂解和多聚腺苷酸化特异性因子6(CPSF 6)是一种细胞蛋白,
在细胞和病毒生物学中的多种功能。我们最近发现CPSF 6控制着细胞的稳定性和活性,
PP 2A,一种直接参与CDK 9和RNA Pol II去磷酸化和失活的磷酸酶,
揭示了一个令人兴奋的新的调查线潜在的治疗策略。这项建议将侧重于以下方面
创新方向:(a)进一步了解调节HIV-1转录的因素,重点是CPSF 6
和PP 2A;(B)探索使用PP 2A抑制作为重新激活潜伏病毒的方法的可能性;和(3)
基于我们小组最近的蛋白质组学实验,进一步探索CPSF 6的未知功能
产生了几个令人兴奋的点击。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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VICENTE PLANELLES其他文献
VICENTE PLANELLES的其他文献
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- 资助金额:
$ 23.1万 - 项目类别:
An Ex Vivo Model of HIV-1 Latency and Reactivation using Primary Memory Cells
使用原代记忆细胞的 HIV-1 潜伏期和再激活的离体模型
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8418764 - 财政年份:2010
- 资助金额:
$ 23.1万 - 项目类别:
An Ex Vivo Model of HIV-1 Latency and Reactivation using Primary Memory Cells
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- 资助金额:
$ 23.1万 - 项目类别: