HHV 8 AND KAPOSIS SARCOMA

描述：（改编自申请人的摘要）卡波西肉瘤（KS）是一种 经常使HIV-I临床病程复杂化的多灶性肿瘤 积极的个人。 由于艾滋病患者的寿命更长， 治疗减少他们的HIV-1病毒载量，继发性肿瘤， KS和非霍奇金淋巴瘤正变得越来越常见， 临床医生 打击KS的一个重要问题是缺乏 确定明确的病原体，以及缺乏 包含所有相关人类细胞成分的动物模型 KS病变。 事实上，KS是一种复杂的肿瘤， 几种不同的细胞类型包括增殖的梭形肿瘤 细胞、内皮细胞和真皮树突细胞。 最近，一种新的DNA 病毒已被认为是一种合理的病原体（即人 疱疹病毒-8; HHV-8），并开发了SCID-人皮肤移植程序。 在这项提议中，这些进展被结合起来，以确定HHV-8是否可以 在这种新的动物模型系统中引起皮肤KS损伤。 一旦HHV-8 将特定的细胞类型引入移植的全层人类皮肤中， 被感染并支持病毒DNA和RNA的产生， 使用高度敏感和特定的定位技术进行识别。 在 此外，细胞因子在HHV-8诱导的KS中的作用将用 特别强调诱导血管生成和可膨胀肿瘤 阵 体内潜在间充质细胞靶点的范围和 将测定HHV-8的体外免疫调节作用， 将检查药物对KS损伤形成的多步骤过程的影响。 为了解决KS有效治疗方式的空白，特别是 在艾滋病的背景下，该动物模型系统将用于测试 抗疱疹药物在预防或逆转KS病变方面的功效。 通过在未来4年内成功完成所有4个目标， 了解这种常见的，神秘的， 可能致命的肿瘤

DESCRIPTION: (Adapted from Applicant's Abstract) Kaposi's sarcoma (KS) is a multifocal neoplasm that frequently complicates the clinical course of HIV-I positive individuals. As AIDS patients are living longer due to better treatment with reduction of their HIV-1 viral load, secondary tumor such as KS and non-Hodgkins lymphomas are becoming more common and problematic for clinicians. A significant problem in combating KS has been lack of identification of a clear-cut etiological agent, as well as absence of an animal model that contains all of the relevant human cellular constituents of KS lesions. Indeed, KS is a complex neoplasm that features participation of several different cell types including proliferating spindle-shaped tumor cells, endothelial cells, and dermal dendritic cells. Recently a novel DNA virus has been suggested as a plausible etiological agent (i.e. human herpesvirus-8; HHV-8), and a SCID-human skin grafting procedure developed. In this proposal, these advances are combined to determine if HHV-8 can cause cutaneous KS lesions in this novel animal model system. Once HHV-8 is introduced into engrafted full-thickness human skin, specific cell types that become infected and support viral DNA and RNA production will be identified using highly sensitive and specific localization techniques. In addition, the role of cytokines in HHV-8 induced KS will be examined with specific emphasis on induction of angiogenesis and expansile tumor formation. The range of potential mesenchymal cell targets in-vivo and in-vitro for HHV-8 will be determined, the influence of immunomodulatory agents on the multi-step process of KS lesion formation will be examined. To address the void in effective treatment modalities for KS, particularly in the setting of AIDS, this animal model system will be used to test the efficacy of anti-herpes agents at either preventing or reversing KS lesions. By successfully completing all 4 aims over the next 4 years, a better understanding of the etiology and pathophysiology of this common, enigmatic, and potentially deadly neoplasm will be had