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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（由申请方提供）：小RNA在先天免疫和炎症中的作用宿主对病毒的应答涉及先天和适应性免疫机制的激活。由宿主防御反应受损引起的病毒持续存在是炎症的常见原因。一些研究表明，病原体的存在可以刺激炎症介导的肿瘤发展。因此，我们的长期目标是了解参与抗病毒反应的宿主信号传导机制的调节，以及先天免疫过程失调引起的慢性炎症如何促进肿瘤发生。病毒在感染细胞中被核酸识别Toll样受体（TLR）或胞质Rig-I样受体（RLR）识别。对病毒的早期反应包括产生I型干扰素（IFN），其继而诱导IFN刺激基因（ISG）的转录并激活阻碍病毒复制的酶。病毒感染也上调其他细胞因子，可以增强先天性和适应性免疫反应。在病毒感染期间，代表病毒基因组或作为复制中间体产生的双链RNA（dsRNA）激活IFN-诱导型2 '，5'-寡腺苷酸合成酶（OAS），其将细胞ATP转化为独特的2 '，5'-连接的寡腺苷酸，2-5A。2-5A的三聚体和四聚体寡聚体激活普遍存在的和潜在的核糖核酸内切酶RNase L，其在UpAp和UpUp部分的3 '末端切割RNA的病毒和细胞单链区域，从而释放具有双链体结构的小RNA。我们最近报道，这些小的“自我”RNA（由RNase L作用产生的细胞RNA的切割产物）可以通过诱导IFN-γ合成来增强抗病毒先天免疫。我们的初步数据使我们假设RNase L激活产生的小RNA也诱导促炎细胞因子和促凋亡途径。这一假设是基于以下观察结果：RNase L的激活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，3）激活凋亡信号通路。鉴定与此过程相关的小RNA可以为开发新的抗肿瘤和抗病毒治疗策略提供基础。具体目的是：1）研究RNase L的小RNA切割产物启动的信号通路。 2)RNA酶L产生的小细胞RNA的克隆和鉴定。 3)开发小RNA作为免疫刺激剂。了解RNase L产生的小RNA在宿主反应中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：宿主对病毒的过度反应可能导致不受控制的炎症，从而导致组织损伤和可能的自身免疫反应，而反应不足则允许病毒传播及其相关的细胞病变。我们的工作特别关注宿主蛋白RNase L在先天免疫反应中的作用，在这项研究中，我们希望进一步了解RNase L产生的小RNA在诱导促炎细胞因子和抗肿瘤或促凋亡基因中的作用。

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。