Mechanism of KSHV-induced angiogenesis

KSHV诱导血管生成的机制

• 批准号: 8311370
• 负责人: Shou-Jiang Gao
• 金额: $ 25.31万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311370
• 关键词: Acquired Immunodeficiency Syndrome; Angiogenesis Inhibition; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Angiogenesis Pathway; Angiogenic Factor; Angiopoietin-2; Animal Model; Animals; Antibodies; Biological Assay; Cell Proliferation; Complex; Development; Disease; Endothelial Cells; Gene Expression; Genes; Genome; Goals; Growth; Health; Human; Human Herpesvirus 8; Image; Immunohistochemistry; Indium; Individual; Infection; Infiltration; Inflammation; Inflammatory; Interleukin-6; Interstitial Collagenase; Kaposi Sarcoma; Knock-out; MEKs; Malignant Neoplasms; Maps; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Monitor; Morbidity - disease rate; Neoplasms in Vascular Tissue; Open Reading Frames; Oral; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Prevention; Preventive; Process; Proliferating; Recombinants; Regulation; Repression; Research; Role; SECTM1 gene; Societies; Spindle Endothelial Cell; Staging; System; Testing; Therapeutic; Time; Tissues; Transcription Factor AP-1; Transcriptional Regulation; Tumor Angiogenesis; Umbilical vein; Viral; Viral Genes; Viral Genome; Viral Proteins; Virus Diseases; Work; angiogenesis; base; cancer therapy; cellular targeting; expectation; in vivo; inhibitor/antagonist; innovation; insight; interdisciplinary approach; latent infection; mortality; mutant; novel; paracrine; programs; promoter; reconstitution; therapeutic target; tumor; tumor growth; tumorigenesis

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.

描述（由申请人提供）：Kaposi'Sarcoma（KS）是AIDS患者中最常见的癌症，与Kaposi肉瘤相关的疱疹病毒（KSHV/HHV8）感染有关。 KS是一种高度血管生成的血管肿瘤，主要由具有广泛炎症性浸润的增殖纺锤体内皮细胞组成。我们的研究计划的长期目标是了解KSHV诱导的发病机理的分子机制，从而为开发有效的预防和治疗方法提供了科学基础。最近的研究表明，血管生成和炎症是KS发病机理中的两个中心成分，而KSHV感染通过旁分泌机制通过诱导亲血管生成和炎症因子来调节这些过程。该应用的目的是定义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标。我们的初步研究表明，人脐静脉内皮细胞的KSHV感染诱导了促血管生成因子的分泌，并抑制了血管生成抑制剂的分泌。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（MMP-1）高度诱导KSHV，并且在KS肿瘤中也高度表达。值得注意的是，我们已经表明，用中和抗体单独阻断Ang-2会在体内废除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，结果，针对这些血管生成途径可以抑制KSHV诱导的肿瘤发生。为了检验这一假设，我们将确定KSHV调节的促血管生成因子和血管生成抑制剂对KSHV诱导的血管生成必不可少的（AIM I）；确定潜在感染中介导ANG-2，IL-6和MMP-1的KSHV调节的细胞途径（AIM II）；并确定调节ANG-2表达的病毒基因（AIM III）。最后，我们将测试在肿瘤动物模型中抑制KSHV诱导的特定血管生成途径的治疗应用（AIM IV）。拟议的项目具有创新性，因为它将使用全面的多学科方法来鉴定病毒和细胞途径，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。这些研究很重要，因为它不仅可以定义KSHV诱导的血管生成的机制，而且还确定了KSHV诱导的恶性肿瘤的潜在治疗靶标。公共卫生相关性：Kaposi的肉瘤是美国艾滋病患者的普遍恶性肿瘤，全世界对社会造成了发病率和死亡率。该项目将调查强调卡波西肉瘤发展的机制，并确定预防和治疗该疾病的潜在靶标。