(PQ 6) New Models of KSHV Oncogenesis and KS Immune Environment

工程 摘要 卡波西‘s 常见 (KSHV、 卡斯特尔曼的 与KSHV关联 单元格 相关 的 众多 vbl.已 表面上 例如 将要 肉瘤(KS)是全球艾滋病毒携带者中最常见的癌症，也是 撒哈拉以南非洲的癌症，由卡波西肉瘤疱疹病毒感染引起 也称为HHV-8)。该病毒还可引起原发渗出性淋巴瘤(PEL)和多中心 疾病(MCD)。虽然PEL很罕见，但它是一种侵袭性的恶性肿瘤，几乎没有治疗选择。 疾病很难建模，因为这种病毒是特定于物种的，它不会转化 在体外培养中，体外感染经常导致潜伏和裂解病毒基因的混合表达，并且 动物病毒不会引起同样的病理。此外，KS病变由一种混合物组成 包括潜伏感染KSHV的梭形细胞和混合炎性浸润物的细胞，包括 CD8和CD4T细胞、浆细胞、巨噬细胞和肥大细胞。虽然大量的关注已经 对于梭形细胞的组织发生，KS皮损中的免疫渗入仅被 和不完全的描述。首要目标是在体外开发这种应用的临床前阶段， KSHV相关疾病的体内和体内模型，包括KS、MCD和淋巴瘤。为了模拟KS，我们 应用于对人类病变的观察，并包括这种疾病的免疫因素。这将是 通过以下具体目标完成：1)主要潜伏期转录本基因的条件表达 具有免疫能力的小鼠；2)检查 工程合成、体外和体外卡波西肉瘤样组织 用于健康和患病的原代内皮细胞受控生长的利基环境。我们将研究以下方面的影响 这些模型中的一线治疗方法、靶向治疗和免疫治疗，以验证它们是否适用于 临床前使用。 重大 免疫 子集 在……里面 小鼠； 肿瘤免疫环境在KS患者皮损中的作用及检验 和3)

PROJECT SUMMARY Kaposi's common (KSHV, Castleman's KSHV-associated cells related of numerous been superficially ex will sarcoma (KS) is the most common cancer globally in people living with HIV, and among the most cancers in Sub-Saharan Africa, and is caused by infection by the Kaposi sarcoma herpesvirus also called HHV-8). This virus also causes primary effusion lymphoma (PEL) and multicentric disease (MCD). While PEL is rare, it is an aggressive malignancy with few therapeutic options. diseases are difficult to model because this virus is species-specific, it does not transform in in culture, in vitro infection frequently leads to a mixture of latent and lytic viral gene expression, and animal viruses do not cause the same pathologies. Furthermore, KS lesions are composed of a mixture cells that include latently KSHV-infected spindle cells and a mixed inflammatory infiltrate that includes CD8+ and CD4+ T cells, plasma cells, macrophages, and mast cells. While substantial attention has given to the histogenesis of the spindle cells, the immune infiltrates in KS lesions have only been and incompletely described. The overarching goal is this application is develop preclinical in vitro, vivo and in vivo models of KSHV-associated diseases, including KS, MCD and lymphoma. To model KS, we applyobservations from human lesions, and include the immune elements of this disease. This will be accomplished through the following specific aims: 1) conditional expression of major latency transcript genes in immunocompetent mice; 2) examine of engineer synthetic, in vitro and ex vivo Kaposi sarcoma-like tissue niches for controlled growth of healthy and diseased primary endothelial cells. We will examine the effects of first line therapeutic approaches, targeted therapy and immunotherapy in these models to validate them for preclinical use. major immune subsets in mice; the tumor immune environment in KS lesions in patients and test the role and 3)