TREATMENT OF VIRUS ASSOCIATED PROLIFERATIVE DISORDERS

芬格罗思博士是一名临床医生兼科学家，致力于以患者为中心的研究。该实验室研究嗜淋巴疱疹病毒(EBV和最近的HHV-8)，这种病毒会在受损的宿主中引起增殖性疾病，并与几种人类肿瘤有关。组织实验室研究，从基础观察到转化研究，再到临床方案的开发。Fingeroth博士指导了几位年轻的临床和基础科学研究人员，他们后来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，信息部也提供了极好的资源。迪什。在BWH/DFCI。拟议的以患者为导向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确定根除病毒感染的人类肿瘤的新机制。这将通过芬格罗思博士指导的综合研究来实现，她将至少投入50%的时间进行这项工作。虽然DNA肿瘤病毒编码的基因产物能够摧毁病毒感染的细胞，但这些基因在永生/致瘤感染期间是沉默的。疱疹病毒合成了许多蛋白质，这些蛋白质支持有效复制病毒DNA所需的核酸合成和蛋白质处理功能。病毒酶的独特性质使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转化为具有高度特异性的细胞毒性化合物。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)。这个以患者为中心的项目的目的是从EBVTK和相关的早期复制产品开始，识别伽玛疱疹病毒蛋白，为细胞毒性抗肿瘤治疗提供合理的靶点。这将通过以下方法实现：(1)通过研究根据与α/β疱疹病毒同源性预测的伽马疱疹病毒蛋白的特性作为抗病毒治疗的靶点-并记录它们这样做-(2)通过确定编码这些蛋白的基因是如何调节的，以便增强它们在病毒感染的肿瘤中的表达；(3)通过体外测试EBV相关淋巴增殖性疾病的动物模型的结果；以及(4)根据这些发现制定临床方案，以最大限度地减少概念验证和患者有空之间的时间。通过抗病毒治疗特异性地破坏EBV感染的淋巴细胞可以为根除EBV感染的细胞提供一种重要的新机制，就像在B淋巴增生性疾病中一样。这项研究还可能有助于对EBV早期基因调控的基本了解，并识别其他潜在的细胞毒效应蛋白，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.