Regulation of Innate Immune Responses

我们的目标是进一步了解先天免疫信号的机制，并澄清 某些致癌病毒如HTLV-1和HHV8可能通过哪些机制颠覆这些重要的 信号通路。我们相信，阐明这些过程将对 对发病机制的认识及新型治疗方法和疫苗的开发 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 感染仍未完全确定，最近有报道称DExD/H盒RNA解旋酶RIG-I (Refinoic酸诱导基因-1)和MDA5(黑色素瘤分化抗原5)是黑色素瘤的关键分子 识别病毒dsRNA物种以触发先天免疫反应。Importanfiy、我们的和其他数据 确认分子RIP1也是促进DExD/H盒介导的信号转导所必需的。值得注意的是， 我们观察到HTLV-1和HHV-8编码的Tax和vIRFI可能分别抑制这些重要的 可以解释病毒致病性的途径、机制和潜伏期模式。鉴于这些数据，我们的目标是 要执行以下操作： L)我们最近发现线粒体蛋白GRIM19/B16.6与RIG-I和MDA5相关。 鉴于此，我们的目标是探索GRIM19/B16.6在先天信号传递过程中的重要性，包括 人乳头瘤病毒8vIRFI和人乳头瘤病毒E6的电位抑制。 II.)我们已经证明了RIP1在促进RIG-I/MDA5信号转导中的重要作用。我们的数据也 表示RIP1可以绑定到GRIM19以及HTLV-1税。因此，我们的目标是进一步研究 RIP1在先天信号中的重要性以及肿瘤病毒蛋白税的潜在抑制作用。 三、)鉴于我们已经观察到税收抑制了先天免疫信号，而先天信号是 HTLV-1诱导的ATL存在缺陷。我们的目标是评估VSV作为一种溶瘤剂在治疗这种疾病中的应用。 疾病。这些治疗方法是根据从AIMS I和II获得的数据设计的。 我们期待这些研究将提高我们对肿瘤学的认识，并为 新药和疫苗策略的合理设计。 相关性(请参阅说明)： 先天免疫反应是机体对病毒感染产生有效免疫反应的关键。这 Proposal计划了解这些过程以及病毒如何颠覆这些过程 导致疾病。该项目还将利用通过这些研究获得的信息来设计新的 与病毒相关癌症作斗争的治疗学。

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.