TREATMENT OF VIRUS ASSOCIATED PROLIFERATIVE DISORDERS

Fingeroth博士是一名临床科学家，致力于以患者为导向的研究。该实验室研究淋巴性疱疹病毒（EBV和最近的HHV-8），它们在受损宿主中引起增殖性疾病，并与几种人类肿瘤有关。实验室研究从基础观察到转化研究再到临床方案的制定。Fingeroth博士指导了几位年轻的临床和基础科学研究人员，他们在以患者为导向的研究中发展了独立的职业生涯。她的实验室得到了支持，并在BWH/DFCI的Inf. dis部门获得了优秀的资源。拟议的面向患者的项目的长期目标是建立一个调查小组，致力于根据病毒的生物学特性确定根除病毒感染的人类肿瘤的新机制。这将通过由Fingeroth博士指导的综合研究来实现，她将至少投入50%的时间来完成这项工作。虽然DNA肿瘤病毒编码的基因产物能够破坏病毒感染的细胞，但这些基因在永生化/致瘤性感染过程中是沉默的。疱疹病毒合成许多支持核酸合成和有效复制病毒DNA所需的蛋白质加工功能的蛋白质。病毒酶的独特性质使得抗病毒药物的开发成为可能，这些药物可以在病毒感染的细胞中具有很强的特异性转化为细胞毒性化合物。其中一些病毒蛋白构成了细胞毒性基因治疗的基础（即HSV TK和更昔洛韦）。这个以患者为导向的项目的目的是鉴定γ疱疹病毒蛋白，从EBVTK和相关的早期复制产物开始，为细胞毒性抗肿瘤治疗提供合理的靶点。这将通过以下方式实现：(1)研究通过与α / β疱疹病毒同源性预测的γ疱疹病毒蛋白作为抗病毒治疗靶点的特性，并记录它们的作用；(2)确定编码这些蛋白的基因如何被调节，以增加它们在病毒感染肿瘤中的表达；(3)在ebv相关淋巴增生性疾病的动物模型中进行体外结果测试；(4)基于该模型制定临床方案这些发现最大限度地缩短了概念证明和患者可用性之间的时间。抗病毒治疗对eb病毒感染淋巴细胞的特异性破坏可能为根除eb病毒感染细胞（如B淋巴细胞增殖性疾病）提供重要的新机制。该研究还可能对EBV早期基因调控的基本认识做出重要贡献，并确定其他潜在的细胞毒性效应蛋白，用于治疗病毒感染、病毒相关肿瘤和基因治疗。

Dr. Fingeroth is a clinician-scientist dedicated to patient-oriented research. The laboratory studies lymphotrophic herpesviruses (EBV and more recently HHV-8) that cause proliferative disorders in the compromised host and that are associated with several human tumors. Laboratory studies are organized to proceed from basic observations to translational research to the development of clinical protocols. Dr Fingeroth has mentored several young clinical and basic science investigators that have gone on to develop independent careers in patient-oriented research. She has support for her laboratory and excellent resources in the Division of Inf. Dis. at BWH/DFCI. The long-term goal of the proposed patient-oriented project is to develop an investigative group dedicated to identifying new mechanisms for eradicating virus infected human tumors based on the biology of the virus. This will be achieved through integrated studies directed by Dr. Fingeroth who will commit a minimum of 50 percent of her time to this effort. Although DNA tumor viruses encode gene products that are capable of destroying virus infected cells, these genes are silent during immortalizing/tumorigenic infection. Herpesviruses synthesize many proteins that support nucleic acid synthesis and protein processing functions required for efficient replication of viral DNA. The unique properties of viral enzymes has permitted development of antiviral drugs that can be converted to cytotoxic compounds with great specificity in virus infected cells. Some of these viral proteins form the basis of cytotoxic gene therapy (i.e. HSV TK and ganciclovir). The aims of this patient-oriented project are to identify gamma herpesvirus proteins, beginning with EBVTK and related early replicative products, that provide rational targets for cytotoxic anti-tumor therapy. This will be achieved by (1) by investigating the properties of gamma herpesvirus proteins predicted by homology to alpha/beta herpesviruses to function as targets for antiviral therapy - and documenting that they do so (2) by determining how the genes encoding these proteins are regulated in order to augment their expression in virus-infected tumors (3) by testing in vitro results in an animal model of EBV-associated lymphoproliferative disease and (4) by generating clinical protocols based on these findings to minimize the time between proof of concept and patient availability. Specific destruction of EBV infected lymphocytes by antiviral therapy could provide a significant new mechanism for eradicating EBV infected cells as in the case of B lymphoproliferative disease. The study is also likely to contribute significant knowledge in the basic understanding of EBV early gene regulation, and to identify other potentially cytotoxic effector proteins for treatment of virus infections, virus associated tumors and for gene therapy.