Interplay Between KSHV and PDGFRA in AIDS-Kaposi's Sarcoma Oncogenesis

KSHV 和 PDGFRA 在艾滋病-卡波西肉瘤肿瘤发生中的相互作用

• 批准号: 9210609
• 负责人: Pascal J. Goldschmidt-Clermont
• 金额: $ 45.72万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9210609
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Animal Model; Anti-Retroviral Agents; Biological; Biology; Cancer Etiology; Cells; Characteristics; Clinical Research; Development; Drug Combinations; Gene Targeting; Genes; Genetic; Genetic Transcription; HIV; Herpesviridae; Herpesviridae Infections; Human; Individual; Integration Host Factors; Kaposi Sarcoma; Lead; Lesion; Local Therapy; Lytic; Lytic Phase; Malignant Neoplasms; Mediating; Mesenchymal Stem Cells; Molecular; Mus; Oncogenes; Oncogenic; Oral cavity; PDGFRA gene; PDGFRB gene; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Platelet-Derived Growth Factor; Principal Investigator; Recruitment Activity; Resistance; Role; Sampling; Signal Transduction; Stem cells; Testing; Therapeutic; Tumor Biology; Viral; Virus; Work; angiogenesis; base; cancer type; chemotherapy; in vivo; inhibitor/antagonist; new therapeutic target; novel; novel strategies; novel therapeutic intervention; paracrine; prevent; progenitor; programs; public health relevance; response; success; targeted treatment; transcriptome; transcriptome sequencing; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): Kaposi' s sarcoma (KS), caused by the KS herpesvirus (KSHV) is an AIDS-associated malignancy (AIDS-KS) and is the most important malignancy of the oral cavity in HIV infected individuals. KS can be treated with local therapy, anti-retroviral therapy and chemotherapy; however, it is estimated more than a half of KS patients will not be cured. KS is characterized by the proliferation of spindle cells and deregulated angiogenesis caused by KSHV genes. The limited success of targeted pathogenesis-based therapies in AIDS- KS such as the use of mTORC1 and PDGFR inhibitors indicate the urgent need to increase our understanding of the interplay of viral and host factors underpinning KS oncogenesis for development of targeted therapies; and more importantly, to inform current therapies. Using animal models of Rac1-dependent and of KSHV- dependent KS oncogenesis developed in our lab, we molecularly delineate an oncogenic paracrine axis connecting the expression of the KSHV oncogene vGCPR with secretion of the paracrine factors in order to define novel therapeutic targets. Novel studies carried out in an unbiased manner led us to: 1) Identify PDGFR- alpha (PGFRA) as the most potent oncogenic driver signaling cascade activated in KS pointing to PDGFRA as a target for anti-KS therapies 2) Identify PDGFRA+ mesenchymal stem cells (MSC) as potential KS oncogenic progenitors. We hypothesize that the prominent activation of PDGFRA and its driver role in the tumors is a consequence of the intrinsic ability of KSHV to target this pathway to increase infectivity, persistence and replication in PDGFRA+ target MSC. (AIM 1) Will study the role of PDGFRA in KSHV infection of PDGFRA+ MSC KS progenitors and oncogenesis: (AIM 2) Will Identify host viral interactions conducive to sustained activation of PDGFRA. (Aim 3) Will seek to use genetic and drug inhibition studies and NGS (RNASeq) to identify and targeting mechanisms of PDGFRA-mediated tumorigenesis in KSHV infected tumors. This work will: 1) Identify phenotypic characteristics of the KS progenitor and how the biology of KSHV in these cells leads to oncogenesis 2) Identify key pathogenic mechanisms and new therapeutic approaches 3) Understand the interplay between PDGFRA and KSHV biology in KS tumors and how it affects pathogenesis and response to therapy

 描述（由适用提供）：由KS疱疹病毒（KSHV）引起的Kaposi的肉瘤（KS）是与AIDS相关的恶性肿瘤（AIDS-K），是HIV感染个体口腔最重要的恶性肿瘤。可以通过局部疗法，抗逆转录病毒疗法和化学疗法来治疗KS；但是，估计将无法治愈一半以上的KS患者。 KS的特征是纺锤体细胞的增殖和由KSHV基因引起的失控血管生成。在AIDS-KS（例如使用MTORC1和PDGFR抑制剂）中，基于发病机理的疗法的成功有限，这表明迫切需要增加我们对基于KS Onceogenesewiss的相互作用和宿主因子相互作用的理解，以开发目标疗法；更重要的是，要通知当前疗法。使用Rac1依赖性和KSHV依赖性KS肿瘤发生的动物模型，我们分子描绘了一个连接KSHV Oncogene VGCPR表达的致癌旁分泌轴与旁分泌因子分泌的表达，以定义新的治疗靶标。以公正的方式进行的新型研究导致我们：1）将PDGFR-Alpha（PGFRA）识别为在KS中激活的最潜在的致癌驱动器信号传导级联反应，指向PDGFRA作为抗KS疗法的靶标2）鉴定PDGFRA+间充充形干细胞（MSC）的潜在识别为潜在的KSS orcentoric oncogen ofcenitors orcenitors。我们假设PDGFRA的显着激活及其在肿瘤中的驱动力作用是KSHV靶向这种途径以增加感染，持久性和复制PDGFRA+目标MSC的固有能力的结果。 （AIM 1）将研究PDGFRA在PDGFRA+ MSC KS祖细胞和Oncogensis的KSHV感染中的作用：（ AIM 2）将确定导致PDGFRA持续激活的宿主病毒相互作用。 （AIM 3）将寻求使用遗传和药物抑制研究和NGS（RNASEQ）来识别和靶向PDGFRA介导的KSHV感染肿瘤中PDGFRA介导的肿瘤发生的机制。这项工作将：1）确定KS祖细胞的表型特征，以及这些细胞中KSHV的生物学如何导致造成肿瘤发生2）识别关键的致病机制和新的治疗方法3）了解PDGFRA和KSHV生物学在KS肿瘤中的相互作用以及对病原体和治疗的影响之间的相互作用