HIV 1 TATS PROMOTION OF KAPOSIS SARCOMA

描述（申请人描述）： 首席研究员计划发展他的智力和分析能力， 成为一名成功获得资助的独立调查员。的程序 说教 病毒学和实验室培训， 将使用具有病毒学和免疫学专门知识的调查人员。长 PI的长期目标是建立自己作为一个全国公认的 人类疱疹病毒8型[HHV 8]-卡波西肉瘤生物学研究者。 人类免疫缺陷病毒（HIV-1）或HHV 8单独存在， 与卡波西肉瘤的高发病率无关其合并 然而，存在导致KS的频繁发展。申请人的 假设是HIV-I中KS的发生频率高且具有攻击性。 感染个体的感染是由于HIV-1达特对细胞或HHV 8的直接作用。 初步研究显示达特信号通过与细胞表面整合素结合 受体通过其RGD整合素结合基序的方式，模拟 整联蛋白配体、纤连蛋白和玻连蛋白。调查人员将测试 粘着斑激酶（FAK）的活化和整合素-FAK- 通过沿着整联蛋白阻断Ras-MAP激酶信号通路 途径和使用ras的显性负突变体。进一步的研究将 使用单个外显子达特，其仍然能够反式激活 与全长达特相比，HIV-1启动子，但缺少RGD基序。初始 研究表明达特在体外激活HHV 8复制。 达特 转基因小鼠将用于研究达特是否也促进HHV 8 体内复制 阐明了达特对整合素- 依赖的细胞信号传导和HHV 8复制将提供对HIV的深入了解- 1发病机制，并可能导致确定的网站， 艾滋病毒感染者中最常见的癌症的干预。

DESCRIPTION (Applicant's Description): The Principal Investigator plans to develop his intellectual and analytical skills to become a successfully funded independent investigator. A program of didactic and laboratory training in virology and mentoring by senior investigators with expertise in virology and immunology will be used. The long term goal of the PI is to establish himself as a nationally recognized investigator in Human herpesvirus 8 [HHV8]-Kaposi's sarcoma biology. The presence of either human immunodeficiency virus (HIV-1) or HHV8 alone is not associated with a high frequency of Kaposi's sarcoma. Their combined presence, however, leads to frequent development of KS. The applicants' hypothesis is that the high frequency and aggressiveness of KS in HIV-I- infected individuals is due to a direct effect of HIV-I Tat on cells or HHV8. Preliminary studies show Tat signals through binding to cell surface integrin receptors through its RGD integrin binding motif in a manner that mimics the integrin ligands, fibronectin and vitronectin. The investigators will test for activation of focal adhesion kinase (FAK) and involvement of the integrin-FAK- Ras-MAP kinase signaling pathway by blockade at steps along the integrin pathway and the use of dominant negative mutants of ras. Further studies will employ single exon Tat, which is still competent for trans-activation of the HIV-1 promoter, but lacks the RGD motif, versus full length Tat. Initial studies have shown that Tat activates HHV8 replication in vitro. Tat transgenic mice will be used for studies on whether Tat also promotes HHV8 replication in vivo. The elucidation of the effects of Tat on integrin- dependent cell signaling, and HHV8 replication will provide insights into HIV- 1 pathogenesis in KS and could lead to the identification of sites for intervention in the commonest cancer seen in HIV-1 infected people.