CTD kinases and HIV latency

CTD 激酶和 HIV 潜伏期

基本信息

批准号：
8326787
负责人：
Boris Matija PETERLIN
金额：
$ 33.4万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-08 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8326787
关键词：
Affect Agonist Alternative Splicing Biochemical Genetics Biological Assay C-terminal Cell Line Cells Combined Modality Therapy Complex Cyclins Data Disease remission Dissection Ensure Epigenetic Process Evaluation Gene Targeting Genetic Screening Genetic Transcription Genome HIV HIV-1 Histone Deacetylase Inhibitor IL7 gene Individual Infection Interleukin-15 Interphase Cell Knowledge Laboratories Latent Virus Lymphokines Macaca Macaca mulatta Mediating Messenger RNA Methods Modeling Molecular Mus NF-kappa B Nuclear Export Organ Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phorbol Esters Phosphorylation Phosphotransferases Polyadenylation Positioning Attribute Positive Transcriptional Elongation Factor B Process Proteins Proviruses RNA RNA Polymerase II RNA Processing RNA Splicing Reagent Regulation Replication-Associated Process Residencies Role Serine Signal Transduction T memory cell T-Cell Activation T-Lymphocyte Testing Tissues Transcript Transcriptional Regulation Translations Viral Viral Genome Viral Load result Viral Proteins Vorinostat cell type chromatin remodeling collaboratory cytokine genetic regulatory protein high throughput screening macrophage monocyte purge reactivation from latency simian human immunodeficiency virus tool verdin photosensitizer

项目摘要

CTD kinases are critical for the elongation of HIV transcription and co-transcriptional processing of viral transcripts. They function after chromatin remodeling and before translation of viral proteins. Thus, our project will interface well with those of Greene, Ott and Verdin on epigenetic regulation ofthe integrated provirus. Manipulations that change the HIV epigenome will then be evaluated with respect to their effects on CTD kinases, for which we not only have the reagents but also a greater understanding of their function. It is more than likely that high throughput screens in these other projects will identify compounds that will affect P-TEFb, CycK or CycL complexes, or that will act in concert with agonists that affect primarily these CTD kinases'. In addition, studies by Karn on effects of cellular signaling on P-TEFb and NF-kB will allow us to his latency model to test our ideas on CycK and CycL complexes as well. It is also possible that effects of Nef are not mediated via P-TEFb but rather disregulate subunits of CycK, By differentially affecting HIV splicing and polyadenylation, they might allow more cells to enter proviral latency.

CTD 激酶对于 HIV 转录的延长和病毒转录本的共转录处理至关重要。它们在染色质重塑之后和病毒蛋白翻译之前发挥作用。因此，我们的项目将与 Greene、Ott 和 Verdin 的项目在整合原病毒的表观遗传调控方面很好地结合。然后，我们将评估改变 HIV 表观基因组的操作对 CTD 激酶的影响，为此我们不仅拥有试剂，而且还对其功能有了更深入的了解。这些其他项目中的高通量筛选很可能会鉴定出影响 P-TEFb、CycK 或 CycL 复合物的化合物，或者与主要影响这些 CTD 激酶的激动剂协同作用的化合物。此外，Karn 对细胞信号传导对 P-TEFb 和 NF-kB 影响的研究将使我们能够利用他的潜伏模型来测试我们对 CycK 和 CycL 复合物的想法。 Nef 的作用也有可能不是通过 P-TEFb 介导的，而是通过失调 CycK 的亚基来调节。通过差异化地影响 HIV 剪接和多聚腺苷酸化，它们可能允许更多细胞进入原病毒潜伏期。