Host Defense Regulation and Viral Oncogenesis

描述（由申请人提供）：病毒被认为是人类恶性疾病的第二大原因，占全世界所有癌症的14-20%。与病毒感染相关的人类癌症包括成人t细胞白血病（ATLL-人类t细胞淋巴细胞病毒感染；HTLV-1感染）、非霍奇金淋巴瘤（eb病毒感染）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特定病毒感染引起的恶性疾病造成的。迈阿密大学（UM）医学院在研究这些日益普遍的恶性疾病方面处于独特的地位。从本质上讲，南佛罗里达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群体。鉴于这种情况，我们在迈阿密大学医学院西尔维斯特综合癌症中心（SCCC）组建了一个研究小组，他们是各自领域的病毒肿瘤学和宿主防御调节专家。他们是Glen N. Barber博士、William Harrington Jr.医学博士、Enrique Mesri博士和Ed Harhaj博士。他们都是SCCC病毒肿瘤学项目的成员，由Harrington和Barber教授共同领导。我们的建议侧重于我们团队中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（IFN）途径在自然对抗病毒和恶性疾病中的重要性方面的专业知识。例如，我们最近阐明了先天免疫信号的一个不依赖于收费的分支，这对于诱导IFN和随后的抗病毒和抗肿瘤基因的表达至关重要。不出所料，这些重要的信号通路现在似乎成为越来越多病毒的目标，其结果可能解释病毒对IFN治疗的耐药性、潜伏期和推测性肿瘤发生的机制。我们的建议侧重于进一步研究有效防御宿主的先天免疫信号机制。我们的研究还包括了HTLV-1、HHV8和EBV对这些过程的调控。更具体地说，我们的提案包括三个主要组成部分：项目一，Glen N. Barber博士：宿主防御机制和肿瘤病毒编码基因产物的调节。项目II， William Harrington, Jr.， M.D: HTLV-1的宿主防御调节。项目三，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.