Regulation of Innate Immune Responses

我们的目标是进一步了解先天免疫信号传导的机制， 选择致癌病毒如HTLV-1和HHV 8的机制可能会破坏这些重要的 信号通路我们相信，阐明这些过程将对 了解发病机制和开发新的治疗方法和疫苗， 肿瘤病毒相关的恶性疾病。而识别病毒所需的细胞信号分子 感染仍然是完全确定的，最近有报道说，DExD/H盒RNA解旋酶，RIG-I （亚叶酸诱导基因-1）和MDA 5（黑色素瘤分化抗原5）是黑色素瘤发生的关键因素。 识别病毒dsRNA种类以触发先天免疫应答。重要的是，我们和其他人的数据 证实分子RIP 1也是促进DExD/H盒介导的信号传导所必需的。注意的就是在 我们已经观察到HTLV-1和HHV-8编码的Tax和vIRFI分别可以抑制这些重要的细胞因子， 可能解释病毒致病性和潜伏模式的途径、机制。根据这些数据，我们的目标是 执行以下操作： （图中为L.）我们最近发现，线粒体蛋白GRIM 19/B16.6与RIG-I和MDA 5相关。 鉴于此，我们的目标是探索GRIM 19/B16.6在先天信号传导过程中的重要性，包括 HHV 8 vIRFI和HPV E6的潜在抑制。 二.）我们已经证明RIP 1在促进RIG-I/MDA 5信号传导中是重要的。我们的数据还 表明RIP 1可以与GRIM 19以及HTLV-1 Tax结合。因此，我们打算进一步研究 RIP 1在先天信号传导中的重要性以及肿瘤病毒蛋白Tax的潜在抑制。 三.）鉴于我们已经观察到Tax抑制先天免疫信号传导，并且先天信号传导是 在HTLV-1诱导的ATL中有缺陷。我们的目的是评估使用VSV作为溶瘤剂来治疗这种 疾病这些治疗方法是根据从目标I和II获得的数据设计的。 我们期望这些研究将提高我们对认知的认识，并为认知提供新的概念。 新药和疫苗策略的合理设计。 相关性（参见说明）： 天然免疫应答是机体对病毒感染产生有效应答的必要条件。这 一项提案旨在了解这些过程，以及了解病毒如何破坏这些过程 导致疾病该项目还将利用这些研究所获得的信息， 治疗与病毒有关的癌症。

Our objectives here are to further understand mechanisms of innate immune signaling and clarify mechanisms by which select oncogenic viruses such as HTLV-1 and HHV8 may subvert these important signaling pathways. We believe that elucidafing these processes will have significant impact on understanding pathogenesis and on the development of novel therapeutics and vaccines to combat oncoviral-related malignant disease. While the cellular signaling molecules required for recognizing virus infection remain to be fully defined, it has recently been reported that the DExD/H box RNA helicases, RIG-I (Refinoic acid inducible gene-1) and MDA5 (melanoma differentiation antigen 5) are key players in recognizing viral dsRNA species to trigger innate immune responses. Importanfiy, ours and others data confirm that the molecule RIP1 is also required to facilitate DExD/H box-mediated signaling. Of note is that we have observed that HTLV-1 and HHV-8 encoded Tax and vIRFI, respecfively, may inhibit these important pathways, mechanisms that may explain viral pathogenicity and modes of latency. Given these data, we aim to do the following: l.)We have recently identified that a mitochondrial protein GRIM19/B16.6 associates with RIG-I and MDA5. Given this, we aim to explore the importance of GRIM19/B16.6 in innate signaling processes, including potential suppression by HHV8 vIRFI and HPV E6. II.) We have demonstrated that RIP1 is important in facilitafing RIG-I/MDA5 signaling. Our data also indicates that RIP1 can bind to GRIM19 as well as HTLV-1 Tax. We therefore aim to further study the importance of RIP1 in innate signaling as well as potential repression by the oncoviral protein Tax. III.) Given that we have observed that Tax inhibits innate immune signaling, and that innate signaling is defective in HTLV-1 induced ATL. we aim to evaluate the use of VSV as an oncolytic agent to treat such diseases. Such therapeutic approaches have been designed based on data obtained from Aims I and II. We anticipate that these studies will improve our knowledge of oncognesis and provide new concepts for the rafional design of novel drugs and vaccine strategies. RELEVANCE (See instructions): Innate immune responses are essenfial for mounfing an effecfive host response against virus infecfion. This proposal intends to understand these processes as well as understand how viruses subvert such processes to cause disease. This project will also utilize information gained through these studies to design new therapeutics to combat viral-related cancers.