Mechanism of KSHV-induced angiogenesis

KSHV诱导血管生成的机制

• 批准号: 8012899
• 负责人: Shou-Jiang Gao
• 金额: $ 4.84万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012899
• 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; 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; 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; mortality; mutant; novel; paracrine; programs; promoter; reconstitution; therapeutic target; tumor; tumor growth; tumorigenesis

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.

项目摘要 卡波西肉瘤（KS）是艾滋病患者中最常见的癌症，与感染有关 Kaposi的肉瘤相关疱疹病毒（KSHV/HHV8）。 KS是高度血管生成的血管肿瘤 主要由具有巨大炎症性浸润的增殖纺锤体内皮细胞组成。长期 我们的研究计划的目标是了解KSHV诱导的发病机理的分子机制， 为开发有效的预防和治疗方法提供了科学依据。最近的研究 已经表明，血管生成和炎症是KS发病机理中的两个中心成分，而 KSHV感染通过旁分泌机制调节这些过程，通过诱导亲血管生成和 炎症因素。该应用的目的是定义KSHV诱导的机制 血管生成，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感染诱导了促进性的分泌 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 Angiopoietin-2（Ang-2）是KSHV最高诱导的促血管生成因素之一，也是高度 在KS肿瘤中表达。值得注意的是，我们已经表明，单独阻止Ang-2中和 抗体废除了KSHV诱导的体内旁分泌依赖性血管生成。我们假设KSHV 通过表达特定病毒基因产物，感染通过旁分泌机制诱导血管生成 为了调节细胞血管生成途径，因此，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 因素和血管生成抑制剂对于KSHV诱导的血管生成必不可少（AIM I）；确定细胞 介导这些促血管生成因子和血管生成的KSHV调节的转录途径 抑制剂（AIM II）；并确定调节这些因素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诱导的特定血管生成的治疗应用 肿瘤动物模型中的途径（AIM IV）。拟议的项目具有创新性，因为它将使用 识别病毒和细胞途径的综合多学科方法以及促血管生成 控制KSHV诱导的血管生成的因素/血管生成抑制剂。这些研究很重要 因为它不仅会定义KSHV诱导的血管生成的机制，还可以确定潜力 KSHV引起的恶性肿瘤的治疗靶标。项目叙述 Kaposi的肉瘤是美国艾滋病患者的常见恶性肿瘤，全球造成了发病率和发病率和 对社会的死亡率。该项目将调查强调Kaposi开发的机制 肉瘤，并确定预防和治疗该疾病的潜在靶标。