Mechanism of KSHV-induced angiogenesis

项目摘要 卡波西肉瘤（KS）是艾滋病患者中最常见的癌症，并且与艾滋病病毒感染有关。 卡波西肉瘤相关疱疹病毒（KSHV/HHV 8）。KS是一种高度血管生成的血管性肿瘤 主要由增殖的梭形内皮细胞和大量炎性浸润组成。长期 我们的研究计划的目标是了解KSHV诱导发病机制的分子机制， 为制定有效的预防和治疗方法提供科学依据。最近的研究 已经表明血管生成和炎症是KS发病机制中的两个中心组成部分， KSHV感染通过旁分泌机制调节这些过程，诱导促血管生成和 炎症因子本申请的目的是确定KSHV诱导细胞凋亡的机制。 血管生成，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原- 血管生成因子并抑制血管生成抑制剂的分泌。重要的是，我们发现， 血管生成素-2（Angiopoietin-2，Ang-2）是KSHV诱导的最高的促血管生成因子之一，并且也是KSHV诱导的最高的促血管生成因子。 在KS肿瘤中表达。值得注意的是，我们已经表明，单独阻断Ang-2与中和作用， 抗体在体内消除KSHV诱导的旁分泌依赖性血管生成。我们假设KSHV 感染通过表达特异性病毒基因产物的旁分泌机制诱导血管生成 调节细胞血管生成途径，因此，靶向这些血管生成途径可以抑制 KSHV诱导的肿瘤发生。为了验证这一假设，我们将鉴定KSHV调节的促血管生成因子， KSHV诱导的血管生成所必需的因子和血管生成抑制剂（目的I）;确定细胞 介导KSHV调节这些促血管生成因子和血管生成的转录途径 抑制剂（目的II）;并确定调节这些因子和抑制剂表达改变的病毒基因 (aim III）。最后，我们将测试抑制KSHV诱导的特异性血管生成的治疗应用， 肿瘤动物模型中的通路（目的IV）。该项目是创新的，因为它将使用 全面的多学科方法，以确定病毒和细胞途径， 控制KSHV诱导的血管生成的因子/血管生成抑制剂。这些研究意义重大 因为它不仅将确定KSHV诱导血管生成的机制，而且还将确定潜在的 KSHV诱导的恶性肿瘤的治疗靶点。项目叙述 卡波西肉瘤是美国和全世界艾滋病患者中常见的恶性肿瘤， 对社会的致命性。该项目将调查卡波西氏症发展的机制 肉瘤，并确定预防和治疗这种疾病的潜在目标。

Project Summary 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 suppresses secretion of angiogenesis inhibitors. Importantly, we have found that angiopoietin-2 (Ang-2) is one of the most highly induced pro-angiogenic factors by KSHV, and is 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 transcriptional pathways that mediate KSHV regulation of these pro-angiogenic factors and angiogenesis inhibitors (aim II); and identify viral genes that regulate the altered expression of these factors and inhibitors (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. Project Narrative 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.