Mechanism of KSHV-induced angiogenesis

 描述(申请人提供)：卡波西肉瘤相关疱疹病毒(KSHV)是卡波西肉瘤(KS)和原发渗出性淋巴瘤(PEL)的病原体。尽管进行了高效的抗逆转录病毒治疗，KS仍然是艾滋病患者的主要癌症。KS的发生与广泛的血管生成和炎症密切相关。了解KSHV诱导血管生成和炎症的分子基础可以深入了解KSHV诱导的发病机制，并为开发治疗KSHV相关恶性肿瘤的新的干预方法奠定基础。在目前的筹资期间，我们在实现这一目标方面取得了重大进展。我们已经证明KSHV感染促进了血管生成、炎症和细胞侵袭。此外，我们还表明，免疫补体系统在人类KS肿瘤、KHSV诱导肿瘤发生的新模型的肿瘤以及潜伏的KSHV感染的内皮细胞中被激活。虽然补体系统是宿主抵御感染的第一道防线，但该系统的异常激活往往会导致病理情况。事实上，我们的初步结果表明，KSHV激活补体系统促进了细胞的生长和存活，并诱导了血管生成。这一新应用的目的是进一步剖析补体介导KSHV诱导的血管生成和肿瘤发生的分子机制，并探索靶向补体系统抑制KS发展的治疗应用。中心假设是，KSHV激活补体系统促进血管生成，从而促进KSHV诱导的肿瘤发生，因此，靶向补体系统可以抑制KSHV诱导的恶性肿瘤的发展。我们有体外感染模型和反向遗传学系统，它们特别适合于确定KSHV激活补体系统的结果并描绘潜在的机制。此外，我们最近开发了一种新的KSHV诱导的肿瘤形成模型，该模型对于针对KSHV和KS开发的新型药物的临床前测试特别有用。我们将通过描绘KSHV在潜伏期激活补体系统的机制(目标1)，确定补体介导KSHV诱导的恶性细胞生长、血管生成和炎症的机制(目标2)，并探索靶向补体在KSHV诱导的肿瘤发生模型中的治疗应用(目标3)来检验这一假说。拟议的项目具有很高的创新性，因为这是首次描述KSHV持续感染时补体系统被病毒劫持的情况。会的 明确KSHV诱导血管生成和炎症的新机制。这将有助于明确KSHV劫持补体系统的分子机制，并为KSHV诱导的恶性肿瘤寻找新的干预靶点，具有重要意义。从这些研究中确定的机制也可以应用于其他持续性感染和癌症。

 DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). KS remains as a dominant cancer in AIDS patients despite highly active anti- retroviral therapy. KS development is closely associated with extensive angiogenesis and inflammation. Understanding the molecular basis of KSHV-induced angiogenesis and inflammation could provide insights into the mechanism of KSHV-induced pathogenesis, and serve as the basis for developing novel intervention approaches for KSHV-related malignancies. In the current funding period, we have made significant progresses toward this goal. We have shown that KSHV infection promotes angiogenesis, inflammation and cell invasion. Furthermore, we have shown that the immune complement system is activated in human KS tumors, in tumors of a novel model of KHSV-induced tumorigenesis, and in latent KSHV-infected endothelial cells. While the complement system is the host first line of defense against infections, abnormal activation of the system often results in pathological conditions. Indeed, our preliminary results have shown that KSHV activation of the complement system promotes cell growth and survival, and induces angiogenesis. The objective of this renewal application is to further dissect the molecular mechanism by which complement mediates KSHV-induced angiogenesis and tumorigenesis, and to explore therapeutic application of targeting the complement system for inhibiting KS development. The central hypothesis is that KSHV activation of the complement system promotes angiogenesis contributing to KSHV-induced tumorigenesis, and as a result, targeting the complement system can inhibit the development of KSHV-induced malignancies. We have in vitro infection models and reverse genetics systems that are uniquely suited for determining the outcomes of KSHV activation of the complement system and delineating the underlying mechanism. Furthermore, we have recently developed a novel model of KSHV-induced tumorigenesis that is particularly useful for preclinical testing of novel agents targeting KSHV and KS development. We will test the hypothesis by delineating the mechanism by which KSHV activates the complement system during latency (Aim 1), determining the mechanisms by which complement mediates KSHV-induced malignant cell growth, angiogenesis and inflammation (Aim 2), and exploring the therapeutic application of targeting complement in models of KSHV- induced tumorigenesis (Aim 3). The proposed project is highly innovative because this is the first description of viral hijacking of the complement system in KSHV persistent infection. It will define a novel mechanism of KSHV induction of angiogenesis and inflammation. It is highly significant as it will define the molecular mechanism of KSHV hijacking of the complement system, and identify novel intervention targets for KSHV- induced malignancies. The mechanisms identified from these studies could also be applied to other persistent infections and cancers.