Host Defense Regulation and Viral Oncogenesis

描述(申请人提供)：病毒被认为是人类恶性疾病的第二大原因，占全球所有癌症的14%-20%。与病毒感染相关的人类癌症包括成人T细胞白血病(全人类T细胞淋巴病毒感染；HTLV-1感染)、非霍奇金淋巴瘤(Epstein-Barr病毒；EBV感染)和卡波西肉瘤(人类疱疹病毒8；HHV8感染)。艾滋病毒感染者死亡的一个主要原因也是由选定的病毒感染引起的恶性疾病造成的。迈阿密大学医学院在研究这些日益流行的恶性疾病方面处于独特的地位。从本质上讲，南佛罗里达州是病毒相关癌症的流行地区，拥有世界上最大的此类疾病患者队列。鉴于这种情况，我们在迈阿密大学医学院、密歇根大学西尔维斯特综合癌症中心(SCCC)、密歇根州立大学(UM)组建了一个研究团队，由病毒肿瘤学和宿主防御监管领域的专家组成。他们是Glen N.Barber，Ph.D.，William Harrington Jr.，M.D.，Enrique Mesri，Ph.D.和Ed Harhaj，Ph.D.，他们都是由Harrington和Barber教授共同领导的病毒肿瘤学项目SCCC的成员。我们的建议侧重于我们集团内普遍存在的重叠优势，并利用我们在分析宿主防御和干扰素(干扰素)途径在自然抗击病毒和恶性疾病方面的重要性方面的专业知识。例如，我们最近阐明了一种不依赖于Toll的先天免疫信号，对于诱导干扰素和随后的抗病毒和抗肿瘤基因的表达是必不可少的。不出所料，这些重要的信号通路现在似乎成为越来越多的病毒的靶标，这一结果可能解释了病毒对干扰素治疗的耐药性、潜伏期和推测的肿瘤形成机制。我们的建议侧重于进一步研究对有效的宿主防御至关重要的先天免疫信号机制。我们的研究还包括肿瘤病毒HTLV-1、HHV8和EBV对这些过程的调节。更具体地说，我们的提案包括三个主要组成部分：项目I，Glen N.Barber，Ph.D.：肿瘤病毒编码基因产物的宿主防御和调节机制。项目II，小威廉·哈林顿，医学博士：HTLV-1的宿主防御调节。项目III，Enrique Mesri，Ph.D.：HHV8(KSHV)介导的宿主防御调节。

DESCRIPTION (provided by applicant): Viruses are considered the second most important cause of malignant disease in humans, contributing up to 14-20% of all cancers worldwide. Human cancers associated with virus infection include adult T-cell leukemia (ATLL- human T-cell lymphotropic virus infection; HTLV-1 infection), non-Hodgkins lymphoma (Epstein-Barr Virus; EBV infection) and kaposi's sarcoma (human herpes virus 8; HHV8 infection). A leading cause of death in HIV-infected individuals is also caused by malignant disease induced by selected viral infection. The University of Miami (UM) School of Medicine is in a unique position to study these increasingly prevalent malignant disorders. Essentially, Southern Florida is an endemic area for viral-associated cancers and has the largest cohorts of patients with such diseases in the world. Given this situation, we have assembled a team of investigators at the University of Miami School of Medicine, Sylvester Comprehensive Cancer Center (SCCC), UM, experts in their respective fields of viral oncology and the regulation of host defense. These are Glen N. Barber, Ph.D., William Harrington Jr., M.D., Enrique Mesri, Ph.D., and Ed Harhaj, Ph.D. All are members of the Viral Oncology Program, SCCC, co-headed by Professors Harrington and Barber. Our proposal focuses on overlapping strengths prevalent within our group and takes advantage of our expertise in analyzing host defense and the importance of the interferon (IFN) pathway in naturally combating viral and malignant disease. For example, we have recently elucidated a toll-independent arm of innate immune signaling, essential for the induction of IFN and subsequent expression of anti-viral and anti-tumor genes. These important signaling pathways now appear, unsurprisingly, to be targeted by a growing number of viruses, consequences that may explain mechanisms of viral resistance to IFN therapy, latency and speculatively tumorigenesis. Our proposal focuses on further studying innate immune signaling mechanisms critical for effective host defense. Our study also encompasses the regulation of these processes by the oncoviruses HTLV-1, HHV8 and EBV. More specifically, our proposal comprises three major components: PROJECT I, Glen N. Barber, Ph.D.: Mechanisms of host defense and regulation by oncoviral encoded gene products. PROJECT II, William Harrington, Jr., M.D.: Host Defense regulation by HTLV-1. PROJECT III, Enrique Mesri, Ph.D.: HHV8 (KSHV)-Mediated Regulation of Host Defense.