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Novel Modifiers of Toll-like and RIG-like Receptor Signaling

Toll 样和 RIG 样受体信号传导的新型修饰剂

基本信息

批准号：
8431811
负责人：
Saumendra N Sarkar
金额：
$ 26.79万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-15 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8431811
关键词：
Agonist Asthma Atherosclerosis Cell Line Cells Chemical Modifier Chemicals Clinical Trials Communities Custom Cytokine Activation Cytokine Gene Disease Double-Stranded RNA Effectiveness Enhancers Ensure Future Genes Genetic Goals Host Defense Human IRF3 gene Immune Immune System Diseases Immune response Immune system Immunologic Receptors Individual Infection Infectious Agent Inflammatory Inflammatory Response Institutes Invaded Investigation Libraries Mediating Methodology Microbiology Modification Molecular Bank Molecular Genetics Natural Immunity Organism Pathway interactions Principal Investigator Process Reagent Receptor Activation Receptor Signaling Regulator Genes Reporter Research Rheumatoid Arthritis Sendai virus Sepsis Series Shapes Signal Pathway Signal Transduction Small Interfering RNA Small Molecule Chemical Library Specificity System TLR3 gene TLR7 gene Testing Tissues Toll-like receptors Tretinoin Universities Up-Regulation Virus Diseases antimicrobial base combat defense response drug development drug discovery gene induction helicase high throughput screening human TLR3 protein human TLR7 protein inhibitor/antagonist insight microbial novel pathogen receptor receptor function research study screening sensor small molecule virology

项目摘要

DESCRIPTION (provided by applicant): Innate immunity of an organism is the in born protection against invading pathogens. Innate immune receptors sense components of invading organisms and trigger immune and inflammatory responses to combat infectious agents. In this proposal we intend to target three human innate immune receptors which among others are involved in detecting virus infection. We will use high throughput screening to identify chemical and small interfering RNA modifiers, which will specifically modulate Toll-like Receptor 3, Retinoic acid Inducible gene I and Toll-like receptor 7 signaling pathways. During the course of this investigation, we would like to find efficient modifiers, test their specificity, and make them available to the research community. We have successfully developed and used high throughput screening experiments to target one of the innate immune receptor - Toll-like Receptor 3. Using a cell-based readout system to screen for inhibitors we have identified novel signaling pathways involved in TLR3 mediated IRF3 activation and cytokine induction. In this proposal we will collaborate with University of Pittsburgh Drug Discovery Institute (DDI) to take advantage of the high throughput screening and drug development expertise of DDI to expand our screening efforts. This project will not only generate novel reagents for studying innate immune receptor signaling pathways, but may also provide building blocks for future drug development, which can be used to treat inflammatory diseases caused by virus infection. RELEVANCE: Innate immune receptors are the first line of sensors to recognize various components of invading pathogens and trigger immune and inflammatory responses to combat the infectious agent. We propose to target a few of these receptors which are involved in sensing virus infections, and identify novel reagents capable of modulating the functions of these receptors. Our long-term goal is to use these specific reagents to treat inflammatory and auto-immune diseases, which are caused by over or under-action of these receptors.

描述（由申请人提供）：生物体的先天免疫是对入侵病原体的天生保护。先天免疫受体感知入侵生物体的成分，并触发免疫和炎症反应来对抗感染因子。在本提案中，我们打算以三种人类先天免疫受体为目标，其中包括检测病毒感染。我们将使用高通量筛选鉴定化学和小干扰RNA修饰剂，这些修饰剂将特异性调节toll样受体3，视黄酸诱导基因I和toll样受体7信号通路。在这项研究过程中，我们希望找到有效的修饰剂，测试它们的特异性，并将它们提供给研究界。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Downregulation of IRF4 induces lytic reactivation of KSHV in primary effusion lymphoma cells.

DOI：
10.1016/j.virol.2014.04.020
发表时间：
2014-06
期刊：
VIROLOGY
影响因子：
3.7
作者：
Forero, Adriana;McCormick, Kevin D.;Jenkins, Frank J.;Sarkar, Saumendra N.
通讯作者：
Sarkar, Saumendra N.

What is the oligoadenylate synthetases-like protein and does it have therapeutic potential for influenza?

什么是寡腺苷酸合成酶样蛋白？它是否具有治疗流感的潜力？

DOI：
10.1586/17476348.2015.994608
发表时间：
2015
期刊：
Expert review of respiratory medicine
影响因子：
3.9
作者：
Alcorn,JohnF;Sarkar,SaumendraN
通讯作者：
Sarkar,SaumendraN

OASL-a new player in controlling antiviral innate immunity.

DOI：
10.1016/j.coviro.2015.01.010
发表时间：
2015-06
期刊：
Current opinion in virology
影响因子：
5.9
作者：
Zhu J;Ghosh A;Sarkar SN
通讯作者：
Sarkar SN

Antiviral activity of human OASL protein is mediated by enhancing signaling of the RIG-I RNA sensor.

DOI：
10.1016/j.immuni.2014.05.007
发表时间：
2014-06-19
期刊：
IMMUNITY
影响因子：
32.4
作者：
Zhu, Jianzhong;Zhang, Yugen;Ghosh, Arundhati;Cuevas, Rolando A.;Forero, Adriana;Dhar, Jayeeta;Ibsen, Mikkel Soes;Schmid-Burgk, Jonathan Leo;Schmidt, Tobias;Ganapathiraju, Madhavi K.;Fujita, Takashi;Hartmann, Rune;Barik, Sailen;Hornung, Veit;Coyne, Carolyn B.;Sarkar, Saumendra N.
通讯作者：
Sarkar, Saumendra N.

Could boosting the oligoadenylate synthetase-like pathway bring a new era of antiviral therapy?

促进寡腺苷酸合成酶样途径能否带来抗病毒治疗的新时代？