HHV 8 AND KAPOSIS SARCOMA

描述：(摘自申请者摘要)卡波西肉瘤是一种 经常使HIV-I临床病程复杂化的多灶性肿瘤 积极向上的人。由于艾滋病患者活得更好，他们的寿命更长 减少HIV-1病毒载量的治疗，继发性肿瘤，如 KS和非霍奇金淋巴瘤正变得更加常见和有问题 临床医生。抗击KS的一个重大问题是缺乏 确定明确的病原体，以及没有 包含所有相关人类细胞成分的动物模型 KS病变的比例。事实上，KS是一种复杂的肿瘤，具有参与性。 几种不同的细胞类型，包括增殖性纺锤形肿瘤 细胞、内皮细胞和真皮树突状细胞。最近发现了一种新的DNA 病毒被认为是一种看似合理的病原体(即人类 疱疹病毒-8；HHV-8)，并开发了SCID-人类皮肤移植程序。 在这项提案中，结合这些进展来确定HHV-8是否可以 在这个新的动物模型系统中引起皮肤KS损害。一旦HHV-8病毒被 被引入植入的全厚人皮肤，特定的细胞类型 它们会被感染并支持病毒DNA和RNA的生产 使用高度敏感和特定的定位技术进行识别。在……里面 此外，细胞因子在HHV-8诱导的KS中的作用将通过 特别强调血管生成的诱导和肿瘤的扩张性 队形。体内潜在间充质细胞靶点的范围和 体外测定HHV-8对免疫调节的影响 将检查KS病变形成的多步骤过程中的试剂。 要解决KS有效治疗方式方面的空白，特别是 在艾滋病的背景下，这个动物模型系统将被用来测试 抗疱疹药物在预防或逆转KS病变方面的疗效。 通过在接下来的4年里成功完成所有4个目标，更好的 对这种常见的、神秘的、 潜在的致命肿瘤将会被

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