An Animal Model for Kaposi's Sarcoma

描述（由申请人提供）：卡波西肉瘤（KS）是一种多细胞、血管生成性肿瘤，发生于免疫抑制，包括艾滋病和实体器官移植。尽管在艾滋病治疗和预防方面取得了进展，KS仍然是全球最常见的艾滋病相关恶性肿瘤，并伴有显著的发病率和死亡率。KS的病原体是一种称为卡波西肉瘤相关疱疹病毒（KSHV，也称为HHV 8）的γ疱疹病毒，已在KS病变内的不同细胞类型中鉴定出，包括内皮细胞、巨噬细胞和显示细胞表面标志物独特组合的特征性KS梭形细胞。此外，患者循环B细胞、单核细胞和造血干细胞中KSHV的存在与KS病变的发展和严重程度相关。因此，目前尚不清楚无细胞病毒感染和随后的体内细胞转化是否在肿瘤形成部位从头发生，或者造血细胞是否作为细胞相关病毒从其迁移影响靶组织的主要病毒靶。我们对KS疾病进展的理解中的这一缺点在很大程度上是由于缺乏有效的体内模型来研究在人类免疫系统背景下KSHV感染的自然史。为了解决这些问题，本研究计划的研究目标是双重的：1）开发一种嵌合动物模型，涉及将人类造血组织植入免疫缺陷（SCID）小鼠，以允许存在功能性人类免疫和皮肤组织区室，其分别代表KSHV感染的已知细胞靶点和KS形成的最常见靶组织; 2）应用定量PCR、流式细胞术和免疫组化分析KSHV引入后模型的组成部分，以更好地理解体内系统内初始感染、传播和肿瘤形成的过程。一项密集的研究计划旨在解决这些目标，希望确定治疗和预防这种毁灭性疾病的治疗靶点。

DESCRIPTION (provided by applicant): Kaposi's sarcoma (KS) is a multicellular, angiogenic tumor arising in the setting of immunosuppression, including AIDS and solid organ transplantation. Despite advances in AIDS therapy and prevention, KS remains the most common AIDS-associated malignancy worldwide and carries with it significant morbidity and mortality. The etiologic agent of KS, a gammaherpesvirus known as Kaposi's sarcoma-associated herpesvirus (KSHV, also referred to as HHV8), has been identified in different cell types within KS lesions, including endothelial cells, macrophages and characteristic KS spindle cells that display a unique combination of cell surface markers. Furthermore, the presence of KSHV within circulating B cells, monocytes, and hematopoietic stem cells in patients correlates with the development and severity of KS lesions. Thus, it remains unclear whether cell-free virus infection and subsequent cellular transformation in vivo takes place de novo at the site of tumor formation or, alternatively, whether hematopoietic cells act as primary viral targets from which cell-associated virus migrates to affect the target tissue. This shortcoming in our understanding of KS disease progress is largely due to the absence of an effective in vivo model in which to study the natural history of KSHV infection in the context of an human immune system. To address these issues, the research aims of this research proposal are two-fold: 1) to develop a chimeric animal model involving the engraftment of human hematopoietic tissue into immunodeficient (SCID) mice to allow for the presence of functional human immune and skin tissue compartments, which represent the known cellular targets for KSHV infection and the most common target tissue for KS formation, respectively; 2) to analyze the components of the model following the introduction of KSHV with the application of quantitative PCR, flow cytometry, and immunohistochemistry in an effort to better understand the process of initial infection, dissemination and tumor formation within an in vivo system. An intense research program has been designed to address these aims with the hope of identifying therapeutic targets for the treatment and prevention of this devastating illness.