Role of small RNAs in innate immunity and inflammation

小RNA在先天免疫和炎症中的作用

基本信息

批准号：
7939177
负责人：
Malathi Krishnamurthy
金额：
$ 42.97万
依托单位：
UNIVERSITY OF TOLEDO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-22 至 2013-09-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): ROLE OF SMALL RNAS IN INNATE IMMUNITY AND INFLAMMATION Host responses against viruses involve activation of both innate and adaptive immune mechanisms. Viral persistence, caused by impaired host defense responses, is a common cause of inflammation. Several studies have indicated that presence of pathogens can stimulate inflammation-mediated tumor development. Thus, our long term goal is to understand the regulation of host signaling mechanisms that are involved in antiviral responses and how chronic inflammation arising from dysregulation of innate immune processes can promote tumorigenesis. Viruses are recognized in infected cells by the nucleic acid- recognizing Toll-like receptors (TLRs) or the cytosolic Rig-I-like receptors (RLRs). Early response to viruses includes production of type I interferon (IFN), which in turn induces the transcription of IFN-stimulated genes (ISGs) and activates enzymes that impede viral replication. Viral infections also upregulate other cytokines that can augment both innate and adaptive immune responses. During viral infections, double stranded RNAs (dsRNAs), representing viral genomes or produced as replicative intermediates, activate the IFN- inducible 2',5'- oligoadenylate synthetases (OAS), which convert cellular ATP to unique 2',5'- linked oligoadenylates, 2-5A. Trimeric and tetrameric oligomers of 2-5A activate a ubiquitous and latent endoribonuclease, RNase L, which cleaves viral and cellular single-stranded regions of RNA at the 3'end of UpAp and UpUp moieties, thereby releasing small RNAs with duplex structures. We recently reported that these small 'self'RNAs (cleavage products of cellular RNA generated by the action of RNase L) can amplify antiviral innate immunity by inducing IFN-¿ synthesis. Our preliminary data have led us to hypothesize that small RNAs generated by activation of RNase L also induces pro-inflammatory cytokines and pro-apoptotic pathways. This hypothesis is based on the observations that activation of RNase L 1) induces transcription of ISGs and antitumor genes, 2) induces chemokines and cytokines and 3) activates apoptotic signaling pathways. Identification of the relevant small RNAs involved with this process could provide a basis for development of novel antitumor and antiviral therapeutic strategies. The specific aims are: 1) Investigate the signaling pathway initiated by small RNA cleavage products of RNase L. 2) Clone and identify small cellular RNA generated by RNase L. 3) Develop small RNAs as immune stimulants. Understanding the role of small RNAs generated by RNase L in host response can provide new strategies to suppress viral infection and inflammation. PUBLIC HEALTH RELEVANCE: Excessive host response to virus may lead to uncontrolled inflammation leading to tissue damage and possible autoimmune responses, while an inadequate response allows viral spread and its associated cytopathicity. Our work focuses particularly on the role of the host protein RNase L in innate immune responses, and in this grant we hope to provide further understanding of the role of RNase L-generated small RNAs in inducing proinflammatory cytokines and anti-tumor or pro-apoptotic genes.

描述（由适用提供）：小型RNA在先天免疫和针对病毒的炎症宿主反应中的作用涉及与先天和适应性免疫力学激活。由宿主防御反应受损引起的病毒持久性是炎症的常见原因。几项研究表明，病原体的存在可以刺激感染介导的肿瘤发展。这是我们的长期目标是了解抗病毒反应涉及的宿主信号传导机制的调节，以及因先天免疫过程失调而引起的慢性感染如何促进肿瘤发生。病毒在被核酸识别剂样受体（TLR）或胞质RIG-I样受体（RLR）中识别出感染细胞。对病毒的早期反应包括I型干扰素（IFN）的产生，进而诱导IFN刺激基因（ISG）的转录并激活阻碍病毒复制的酶。病毒感染还会上调其他可以增加先天和适应性免疫治疗的细胞因子。在病毒感染期间，代表病毒基因组或作为复制性中间体产生的双链RNA（DSRNA）激活IFN诱导的2'，5'-- 5'--寡聚腺苷酸合成酶（OAS），这些酶（OAS）将细胞ATP转化为独特的2'，5'-链接的2'，5'-链接的寡聚二腺苷，2-5A。 2-5a的三聚体和四聚体寡聚激活了无处不在的潜在内核酸酶，RNase L，它在3'End of Upap and Upup Meieties中裂解病毒和细胞单链RNA的RNA的单链区域，从而将小型RNA与Duplex结构释放。我们最近报道说，这些小的“自我”（由RNase L的作用产生的细胞RNA的切割产物）可以通过诱导IFN-€合成来扩大抗病毒先天免疫。我们的初步数据使我们假设通过RNase L的激活产生的小RNA还诱导促炎性细胞因子和促凋亡途径。该假设基于以下观察结果：RNase L 1）诱导ISG和抗肿瘤基因的转录，2）诱导趋化因子和细胞因子以及3）激活凋亡信号传导途径。识别与此过程有关的相关小型RNA可以为开发新型抗肿瘤和抗病毒疗法策略提供基础。具体目的是：1）研究由RNase L的小RNA裂解产物引发的信号传导途径。2）克隆并鉴定由RNase L. 3）产生的小细胞RNA。了解RNase L在宿主反应中产生的小RNA的作用可以提供抑制病毒感染和炎症的新策略。公共卫生相关性：过度宿主对病毒的反应可能导致不受控制的炎症，导致组织损伤和可能的自身免疫反应，而反应不足则可以使病毒扩散及其相关的细胞病变。我们的工作尤其着重于宿主蛋白RNase L在先天免疫反应中的作用，在这项赠款中，我们希望进一步了解RNase L生成的小RNA在诱导的促炎细胞因子和抗肿瘤或促脑化基因中的作用。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Epigallocatechin-3-gallate suppresses proinflammatory cytokines and chemokines induced by Toll-like receptor 9 agonists in prostate cancer cells.

DOI：
10.2147/jir.s61365
发表时间：
2014
期刊：
Journal of inflammation research
影响因子：
4.5
作者：
Mukherjee S;Siddiqui MA;Dayal S;Ayoub YZ;Malathi K
通讯作者：
Malathi K

Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant.

DOI：
10.1371/journal.ppat.0020025
发表时间：
2006-03
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Urisman A;Molinaro RJ;Fischer N;Plummer SJ;Casey G;Klein EA;Malathi K;Magi-Galluzzi C;Tubbs RR;Ganem D;Silverman RH;DeRisi JL
通讯作者：
DeRisi JL

ACPR, a STE12 homologue from Candida albicans, is a strong inducer of pseudohyphae in Saccharomyces cerevisiae haploids and diploids.

ACPR 是来自白色念珠菌的 STE12 同源物，是酿酒酵母单倍体和二倍体中假菌丝的强诱导剂。