Mechanism of KSHV-induced angiogenesis

描述(申请人提供)：卡波西肉瘤(KS)是艾滋病患者最常见的癌症，与感染卡波西肉瘤相关疱疹病毒(KSHV/HHV8)有关。KS是一种高度血管生成的血管肿瘤，主要由增殖的梭形内皮细胞组成，并伴有大量的炎性细胞浸润。我们研究计划的长期目标是了解KSHV诱导发病的分子机制，为开发有效的预防和治疗方法提供科学依据。最近的研究表明，血管生成和炎症是KS发病过程中的两个核心组成部分，KSHV感染通过诱导促血管生成因子和炎症因子，通过旁分泌机制调节这两个过程。本应用的目的是明确KSHV诱导血管生成的机制，并确定KSHV诱导的恶性肿瘤的潜在治疗靶点。我们的初步研究表明，KSHV感染人脐静脉内皮细胞可诱导促血管生成因子的分泌，并抑制血管生成抑制因子的分泌。重要的是，我们发现促血管生成因子血管生成素-2(Ang-2)、白介素6(IL-6)和基质金属蛋白酶-1(MMP1)在KSHV诱导下高度表达，在KS肿瘤中也高表达。值得注意的是，我们已经证明，用中和抗体单独阻断Ang-2可以在体内取消KSHV诱导的旁分泌依赖的血管生成。我们假设KSHV感染通过表达特定的病毒基因产物来调节细胞血管生成途径，从而通过旁分泌机制诱导血管生成，因此，靶向这些血管生成途径可以抑制KSHV诱导的肿瘤形成。为了验证这一假说，我们将确定KSHV调节的促血管生成因子和血管生成抑制物对KSHV诱导的血管生成至关重要(Aim I)；确定在潜伏感染中介导KSHV调节Ang-2、IL-6和MMP-1的细胞通路(Aim II)；以及确定调节Ang-2表达的病毒基因(Aim III)。最后，我们将在肿瘤动物模型中测试抑制KSHV诱导的特定血管生成途径的治疗应用(目标IV)。拟议的项目具有创新性，因为它将使用综合的多学科方法来确定病毒和细胞途径，以及控制KSHV诱导的血管生成的促血管生成因子/血管生成抑制剂。这些研究具有重要意义，因为它不仅将确定KSHV诱导血管生成的机制(S)，而且还将确定KSHV诱导的恶性肿瘤的潜在治疗靶点。公共卫生相关性：卡波西氏肉瘤是美国和世界范围内艾滋病患者常见的恶性肿瘤，对社会造成发病率和死亡率。本项目将研究卡波西氏肉瘤的发病机制，并确定预防和治疗这种疾病的潜在靶点。

DESCRIPTION (provided by applicant): Kaposi' sarcoma (KS) is the most common cancer in AIDS patients, and is associated with infection of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8). KS is a highly angiogenic vascular neoplasm primarily consisting of proliferating spindle endothelial cells with vast inflammatory infiltration. The long-term goal of our research program is to understand the molecular mechanism of KSHV-induced pathogenesis, providing a scientific basis for developing effective preventive and therapeutic approaches. Recent studies have shown that angiogenesis and inflammation are two central components in KS pathogenesis, and KSHV infection modulates these processes through a paracrine mechanism by inducing pro-angiogenic and inflammatory factors. The objective of this application is to define the mechanisms by which KSHV induces angiogenesis, and identify potential therapeutic targets for KSHV-induced malignancies. Our preliminary studies have shown that KSHV infection of human umbilical vein endothelial cells induces secretion of pro-angiogenic factors and represses secretion of angiogenesis inhibitors. Importantly, we have found that pro-angiogenic factors angiopoietin-2 (Ang-2), interleukin-6 (IL-6), and matrix metalloproteinase-1 (MMP-1) are highly induced by KSHV, and are also highly expressed in KS tumors. Significantly, we have shown that blocking Ang-2 alone with a neutralization antibody abolishes KSHV-induced paracrine-dependent angiogenesis in vivo. We hypothesize that KSHV infection induces angiogenesis through a paracrine mechanism by expressing specific viral gene products to modulate cellular angiogenic pathways, and as a result, targeting these angiogenic pathways can inhibit KSHV- induced tumorigenesis. To test this hypothesis, we will identify KSHV-regulated pro-angiogenic factors and angiogenesis inhibitors essential for KSHV-induced angiogenesis (aim I); determine the cellular pathways that mediate KSHV regulation of Ang-2, IL-6 and MMP-1 in latent infection (aim II); and identify viral genes that regulate the expression of Ang-2 (aim III). Finally, we will test the therapeutic applications of inhibiting KSHV-induced specific angiogenic pathways in tumor animal models (aim IV). The proposed project is innovative because it will use comprehensive multidisciplinary approaches to identify viral and cellular pathways, and pro-angiogenic factors/angiogenesis inhibitors that control KSHV-induced angiogenesis. These studies are significant because it will not only define the mechanism(s) of KSHV-induced angiogenesis but also identify potential therapeutic targets for KSHV-induced malignancies. PUBLIC HEALTH RELEVANCE: Kaposi's sarcoma is a common malignancy in AIDS patients in US and worldwide inflicting morbidity and mortality to the society. This project will investigate the mechanism underlining the development of Kaposi's sarcoma, and identify potential targets for the prevention and treatment of this disease.