权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cytosolic virus detection in Caenorhabditis elegans

秀丽隐杆线虫胞浆病毒检测

基本信息

批准号：
8824358
负责人：
Rui Lu
金额：
$ 23.02万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-16 至 2016-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): In mammals, including humans, RIG-I-like RNA helicases (RLHs) RIG-I, MDA5 and LGP2 detect invading viral RNAs thereby to initiate an antiviral signaling cascade. Interestingly, although sharing similar domain structure, RIG-I and MDA5 appear to detect RNA viruses of distinct classes. LGP2 is another type of RLH that lacks the N-terminal domains conserved in RIG-I and MDA5 and is known to play a regulatory role in antiviral signaling initiated by RIG-I and MDA5. Currently, whether additional viral molecular patterns are recognized by RIG-I and MDA5 for efficient virus detection by RIG-I and what determines the virus recognition specificity of RIG-I and MDA5 remain largely unknown. Since current studies on the function and mechanism of LGP2 have been generating controversial findings, as a result, how LGP2 regulates the antiviral signaling initiated by RIG-I and MDA5 remains unclear. Our recent observations suggested that RLHs as a three-member family also play important role in antiviral RNA silencing in the nematode Caenorhabditis elegans. Most importantly, one of the worm RLHs, termed DRH-1, appears to contribute to virus detection in a way similar to virus detection by RIG-I. It was also clear from our study that DRH-3, another C. elegans RLH that shares similar domain structure with DRH-1, plays a distinct role in antiviral RNA silencing. The third C. elegans RLH, termed DRH-2, lacks an N-terminal domain found in DRH-1 and DRH-3 and is known to negatively regulate antiviral RNA silencing. Interestingly, DRH-2 functionally replaces the corresponding domains of DRH-1, suggesting that it may specifically regulate the function of DRH-1 in antiviral RNA silencing. Taken together, these observations together establish C. elegans as an ideal model system to study RLH-mediated virus sensing at whole organism level. To better understand how viruses are detected and destroyed by antiviral RNA silencing in C. elegans, here we propose to (1) elucidate the mechanism of DRH-1 in virus sensing by investigating what DRH-1 detects and how the antiviral signal is transmitted to downstream signaling molecules; (2) elucidate the mechanism controlling the function specificity of DRH-1 and DRH-3 by defining a role of DRH-3 in antiviral silencing and viral pathogenesis; (3) determine if DRH-2 specifically targets and regulates the function of DRH-1. Findings from the proposed studies are also expected to (1) identify novel molecular patterns recognized by RIG-I and MDA5; (2) shed light on the mechanism controlling virus recognition specificity of RIG-I and MDA5; (3) have direct input to input to the study of LGP2-mediated regulation of antiviral signaling initiated by RIG-I and MDA5.

描述（由申请人提供）：在包括人类在内的哺乳动物中，RIG-I样RNA解旋酶（RLH）RIG-I、MDA5和LGP2检测入侵的病毒RNA，从而启动抗病毒信号级联。有趣的是，尽管 RIG-I 和 MDA5 具有相似的结构域结构，但它们似乎可以检测不同类别的 RNA 病毒。 LGP2 是另一种类型的 RLH，缺乏 RIG-I 和 MDA5 中保守的 N 端结构域，已知在 RIG-I 和 MDA5 启动的抗病毒信号传导中发挥调节作用。目前，RIG-I和MDA5是否能够识别额外的病毒分子模式以实现RIG-I有效的病毒检测以及决定RIG-I和MDA5的病毒识别特异性的因素仍然很大程度上未知。由于目前对LGP2功能和机制的研究一直存在争议，因此LGP2如何调节RIG-I和MDA5启动的抗病毒信号仍不清楚。我们最近的观察表明，RLH 作为一个三成员家族，在线虫秀丽隐杆线虫的抗病毒 RNA 沉默中也发挥着重要作用。最重要的是，一种名为 DRH-1 的蠕虫 RLH 似乎以类似于 RIG-I 病毒检测的方式有助于病毒检测。我们的研究还清楚地表明，DRH-3（另一种线虫 RLH，与 DRH-1 具有相似的结构域结构）在抗病毒 RNA 沉默中发挥着独特的作用。第三种秀丽隐杆线虫 RLH，称为 DRH-2，缺乏 DRH-1 和 DRH-3 中发现的 N 末端结构域，已知可负向调节抗病毒 RNA 沉默。有趣的是，DRH-2在功能上取代了DRH-1的相应结构域，表明它可能特异性调节DRH-1在抗病毒RNA沉默中的功能。总而言之，这些观察结果共同将线虫确立为在整个生物体水平上研究 RLH 介导的病毒传感的理想模型系统。为了更好地理解线虫中的抗病毒RNA沉默如何检测和破坏病毒，我们建议（1）通过研究DRH-1检测什么以及抗病毒信号如何传递到下游信号分子来阐明DRH-1在病毒传感中的机制； (2)通过定义DRH-3在抗病毒沉默和病毒发病机制中的作用，阐明控制DRH-1和DRH-3功能特异性的机制； (3)确定DRH-2是否特异性靶向并调节DRH-1的功能。拟议研究的结果预计还将 (1) 识别出 RIG-I 和 MDA5 识别的新分子模式； (2)揭示RIG-I和MDA5控制病毒识别特异性的机制； (3) 对 RIG-I 和 MDA5 启动的 LGP2 介导的抗病毒信号传导调节的研究具有直接输入。