Mechanism of KSHV-induced angiogenesis

 描述（由申请方提供）：卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤（KS）和原发性渗出性淋巴瘤（PEL）的病原体。尽管有高效的抗逆转录病毒治疗，KS仍然是AIDS患者的主要癌症。KS的发展与广泛的血管生成和炎症密切相关。了解KSHV诱导的血管生成和炎症的分子基础可以为KSHV诱导的发病机制提供见解，并为开发KSHV相关恶性肿瘤的新干预方法奠定基础。在目前的资助期内，我们在实现这一目标方面取得了重大进展。我们已经表明，KSHV感染促进血管生成，炎症和细胞侵袭。此外，我们已经表明，免疫补体系统被激活的人KS肿瘤，在肿瘤的一种新的模型KHSV诱导的肿瘤，并在潜伏的KSHV感染的内皮细胞。虽然补体系统是宿主抵抗感染的第一道防线，但该系统的异常激活通常导致病理状况。事实上，我们的初步结果表明，KSHV激活补体系统促进细胞生长和存活，并诱导血管生成。本更新申请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，从而导致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，这些模型和系统特别适合于确定KSHV激活补体系统的结果并描述潜在的机制。此外，我们最近开发了一种KSHV诱导的肿瘤发生的新模型，该模型特别适用于靶向KSHV和KS发展的新型药物的临床前测试。我们将通过描述KSHV在潜伏期期间激活补体系统的机制（目的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（目的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（目的3）来验证这一假设。该项目具有高度创新性，因为这是首次描述KSHV持续感染中补体系统的病毒劫持。它将 确定了KSHV诱导血管生成和炎症的新机制。这是非常重要的，因为它将定义KSHV劫持补体系统的分子机制，并确定KSHV诱导的恶性肿瘤的新干预靶点。从这些研究中发现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.