HIV 1 TATS PROMOTION OF KAPOSIS SARCOMA

描述(申请人的描述)： 首席调查员计划发展他的智力和分析能力 成为一名成功资助的独立调查员的技能。一项计划 高年级学生在病毒学和辅导方面的教学和实验室培训 将使用具有病毒学和免疫学专业知识的调查人员。《长河》 PI的任期目标是将自己确立为全国公认的 人类疱疹病毒8型[HHV8]-卡波西肉瘤生物学研究员。 人类免疫缺陷病毒(HIV-1)或HHV8单独存在是 与卡波西肉瘤的高发无关。他们加在一起 然而，存在导致KS的频繁发展。申请人的 假设KS在HIV-I中的高频率和侵袭性- 感染者是由于HIV-I TAT对细胞或HHV8的直接影响。 初步研究表明TAT信号通过与细胞表面整合素结合 受体通过其RGD整合素结合基序以一种模仿 整合素配体、纤维连接蛋白和玻璃体连接蛋白。调查人员将测试 粘着斑激酶(FAK)的激活及整合素-FAK-1的参与 RAS-MAP信号通路沿着整合素的分步阻断 Ras显性负性突变体的途径和利用。进一步的研究将 使用单个外显子TAT，它仍然有能力反式激活 HIV-1启动子，但缺乏RGD基序，而不是全长TAT。首字母 研究表明，TAT在体外激活了HHV8的复制。塔特 转基因小鼠将用于研究TAT是否也能促进HHV8 体内复制。TAT对整合素作用的研究进展 依赖的细胞信号和HHV8复制将提供对HIV- 1在KS中的发病机制，并可能导致确定 对HIV-1感染者最常见的癌症进行干预。

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.