Role of DNA sensing pathways in KSHV associated cancers

DNA 传感途径在 KSHV 相关癌症中的作用

• 批准号: 10247832
• 负责人: Zhe Ma
• 金额: $ 24.51万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247832
• 关键词: Advisory Committees; Antiviral Agents; Antiviral Response; CRISPR/Cas technology; Cell Proliferation; Chemicals; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Core Facility; DNA; Development; Disease; Drug Screening; Drug Targeting; Enhancers; Etiology; Foundations; Herpesviridae Infections; Human; Human Herpesvirus 8; Immune signaling; In Vitro; Infection; Innate Immune Response; Innate Immune System; Interferon Type I; Interferons; Kaposi Sarcoma; Knowledge; Life; Malignant Neoplasms; Mediating; Mentorship; Modeling; Molecular; Multicentric Angiofollicular Lymphoid Hyperplasia; Mus; Natural Immunity; Oncogenic Viruses; Pathogenesis; Pathway interactions; Periodicity; Pharmaceutical Preparations; Population; Primary Infection; Problem Solving; Production; Proteins; Regulation; Reporting; Research; Resources; Role; Screening Result; Signal Transduction; Small Interfering RNA; Solid; Stimulator of Interferon Genes; System; Technology; Testing; Therapeutic; Therapeutic Studies; Training; Treatment Efficacy; Tumor Biology; Validation; Viral; Viral Cancer; Viral Pathogenesis; Viral Proteins; Viral reservoir; Virus; Virus Diseases; Virus Inhibitors; antitumor effect; base; cancer diagnosis; cancer therapy; carcinogenicity; career; cell growth; gammaherpesvirus; in vivo; insight; latent infection; lytic replication; mouse model; neoplastic cell; novel; prevent; primary effusion lymphoma; recombinant virus; response; screening; targeted cancer therapy; tool; tumor; tumor growth; tumor progression; tumorigenesis; vaccine access; viral interferon regulatory factor-1; viral transmission

PROJECT SUMMARY/ABSTRACT Kaposi's sarcoma associated herpesvirus is the etiological agent for several malignancies in the human population including Kaposi's sarcoma (KS), Multicentric Castleman's disease (MCD), and primary effusion lymphoma (PEL). Although innate immunity has been shown to be important for comprehensive antiviral responses to clear viral infection and limit viral tumor growth and proliferation, exactly how the innate immune system senses tumor viruses, such as KSHV, is not well understood at the molecular level. Investigating the interplay between the innate immune system, KSHV and KSHV-associated cancers will help us develop better therapies to not only treat KSHV related malignancies, but also broaden our knowledge to other viral cancers. Previously, we have found that cGAS-STING pathway is responsible for triggering innate immune responses upon KSHV infection. However, KSHV can still establish lifelong infection in the presence of cGAS-STING signaling, suggesting KSHV viral regulation of cGAS- STING pathway to suppress innate immunity. In order to identify potential viral regulators, we have developed a screening system and successfully identified multiple viral proteins that negatively regulate cGAS-STING signaling. We have also validated one of our candidates, vIRF1, and explored the mechanism of how vIRF1 blocks cGAS- STING pathway to facilitate KSHV replication. Our results suggest that modulation of cGAS-STING pathway is important for viral transmission and the lifelong persistence of gammaherpesviruses in the human population. Therefore, studies in this K99/R00 proposal will build upon these findings to extend our knowledge of how these viral proteins regulate cGAS-STING pathway and how to develop potential KSHV cancer therapy by targeting these viral proteins. Specifically, I will focus on: 1) Validating our screening results and exploring detailed mechanisms of cGAS-STING signaling regulation by our KSHV viral candidates, 2) Utilizing multiple technologies, including siRNA, recombinant virus, and CRISPR to explore the role of our viral candidates on KSHV pathogenesis in vitro, 3) Utilizing CRISPR technology to explore the role of our viral candidates in our PEL based mouse model, 4) Screening for drugs that target cGAS-STING pathway, and testing their efficacy in our PEL based mouse model. With strong mentorships and a detailed training plan, I aim to build a solid foundation for a successful independent research career investigating the interaction of cGAS-STING pathway and KSHV cancers and developing potential KSHV cancer treatments.

项目总结/摘要 卡波西肉瘤相关疱疹病毒是人类几种恶性肿瘤的病原体 包括卡波西肉瘤（KS）、多中心Castleman病（MCD）和原发性渗出性淋巴瘤（PEL）。 虽然先天免疫已被证明是重要的全面抗病毒反应，以清除病毒， 感染和限制病毒肿瘤生长和增殖，正是先天免疫系统如何感知肿瘤病毒， 例如KSHV，在分子水平上还没有得到很好的理解。研究先天性免疫与 系统，KSHV和KSHV相关癌症将有助于我们开发更好的治疗方法，不仅治疗KSHV相关癌症， 恶性肿瘤，而且还扩大了我们对其他病毒性癌症的认识。此前，我们发现cGAS-STING 在KSHV感染时，KSHV通路负责触发先天免疫应答。然而，KSHV仍然可以 在存在cGAS-STING信号传导的情况下建立终身感染，表明KSHV病毒调节cGAS- STING途径抑制先天免疫。为了鉴定潜在的病毒调节剂，我们开发了一种 筛选系统，并成功地鉴定了多种负调节cGAS-STING信号传导的病毒蛋白。 我们还验证了我们的候选者之一vIRF 1，并探索了vIRF 1如何阻断cGAS的机制。 STING途径以促进KSHV复制。我们的研究结果表明，cGAS-STING途径的调节是 对于病毒传播和人类群体中γ疱疹病毒的终身持续性很重要。 因此，本K99/R 00提案中的研究将基于这些发现，以扩展我们对这些问题的认识。 病毒蛋白调节cGAS-STING通路，以及如何通过靶向这些蛋白来开发潜在的KSHV癌症疗法。 病毒蛋白具体而言，我将重点关注：1）验证我们的筛选结果并探索详细的机制 cGAS-STING信号调节，2）利用多种技术，包括 siRNA、重组病毒和CRISPR来探索我们的候选病毒在KSHV发病机制中的作用。 3）利用CRISPR技术来探索我们的候选病毒在我们的基于PEL的小鼠模型中的作用， 4)筛选靶向cGAS-STING通路的药物，并在我们的基于PEL的小鼠中测试其功效 模型凭借强大的指导和详细的培训计划，我的目标是为成功建立一个坚实的基础。 研究cGAS-STING途径和KSHV癌症的相互作用的独立研究生涯， 开发KSHV癌症治疗的潜力