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Imaging-base Automated Screen for Compounds that Induce P-TEFb

基于成像的自动筛选诱导 P-TEFb 的化合物

基本信息

批准号：
9352533
负责人：
Andrew P Rice
金额：
$ 23.78万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9352533
关键词：
Agonist Alpha Cell Anti-HIV Agents Antiviral Agents Applications Grants Blood donor CCL19 gene CD4 Positive T Lymphocytes Catalytic Domain Cell model Cells Chemicals Chromatin Coupled Data Down-Regulation Elongation Factor Genes Genetic Transcription Goals HIV HIV Infections HIV-1 Histone Deacetylase Inhibitor Image Image Analysis Immune response Immune system Infection Latent Virus Maintenance Microscopy Modification Pathway interactions Phosphorylation Positive Transcriptional Elongation Factor B Proteasome Inhibitor Proviruses Publications RNA Polymerase II Research Rest Shock Signal Pathway T-Cell Receptor Testing Virus Virus Latency Virus Replication Work base cellular imaging cyclin T1 cytokine experimental study in vivo integration site killings memory CD4 T lymphocyte novel reactivation from latency small molecule synergism therapeutic vaccine transcription factor

项目摘要

Although combinations of anti-HIV drugs can effectively suppress virus replication, a reservoir of cells harboring latent HIV-1 precludes a cure of infection. The best described latent reservoir consists of long-lived memory CD4+ T cells that contain a transcriptionally silent but replication-competent provirus. Multiple mechanisms are involved in the establishment and maintenance of latency, especially limiting levels of the key RNA Polymerase II elongation factor termed P-TEFb. Core P-TEFb consists of Cyclin T1 as a regulatory subunit and CDK9 as the catalytic subunit. The proposed research will optimize and perform an imaging- based automated screen for compounds that induce P-TEFb in resting CD4+ T cells. Compounds that score positive in this screen will be validated in immunoblots for the ability to induce P-TEFb in resting CD4+ T cells, as well as for their ability to function as latency reversal agents in a primary CD4+ T cell model of latency. Compounds identified by this novel screen have the potential to contribute to HIV cure strategies.

虽然抗艾滋病病毒药物的组合可以有效地抑制病毒复制，潜伏的HIV-1使感染无法治愈。描述最好的潜在储层由长期的记忆性CD 4 + T细胞，含有转录沉默但有复制能力的前病毒。多机制参与延迟的建立和维护，特别是限制密钥的级别。 RNA聚合酶II延伸因子称为P-TEFb。核心P-TEFb由细胞周期蛋白T1作为调节因子组成。亚基和CDK 9作为催化亚基。拟议的研究将优化和执行成像- 基于自动化筛选诱导静息CD 4 + T细胞中P-TEFb的化合物。得分的化合物将在免疫印迹中验证该筛选中的阳性在静息CD 4 + T细胞中诱导P-TEFb的能力，以及它们在潜伏期的原代CD 4 + T细胞模型中作为潜伏期逆转剂的能力。通过这种新的筛选鉴定的化合物有可能有助于HIV治愈策略。