Interplay between PDGFRA, oxygen-regulated translation and KSHV in Kaposi's sarcomagenesis

PDGFRA、氧调节翻译和 KSHV 在卡波西肉瘤发生中的相互作用

• 批准号: 10581583
• 负责人: Noula Dattu Shembade
• 金额: $ 45.27万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581583
• 关键词: AIDS therapy; Acquired Immunodeficiency Syndrome; Affect; Binding; Bypass; Cancer Etiology; Cells; Clinical; Compensation; Complex; Development; Disease; Environment; FRAP1 gene; Feedback; Genes; Genetic; HIF1A gene; HIV; Human; Human Herpesvirus 8; Hypoxia; Imatinib; In Vitro; Infection; Kaposi Sarcoma; Lytic; Mediating; Mediator; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Natural Immunity; Oncogenes; Oncogenic; Outcome; Oxygen; PDGFRA gene; PIK3CG gene; Pathogenesis; Pathway interactions; Phosphotransferases; Platelet-Derived Growth Factor; Populations at Risk; Proliferating; Protein Biosynthesis; Proto-Oncogene Proteins c-akt; RNA Cap-Binding Proteins; Regulation; Research; Resistance; Role; Sampling; Signal Transduction; Stress; System; Testing; Therapeutic; Tissues; Translation Initiation; Translational Activation; Translations; Up-Regulation; Viral; Viral Oncogene; Viral Proteins; Virus; Virus Diseases; antiretroviral therapy; design; global health; improved; in vivo Model; insight; novel therapeutics; paracrine; phenotypic biomarker; progenitor; rational design; recruit; repository; targeted treatment; therapeutic target; therapy design; tumor; tumorigenesis

In spite of our understanding of KSHV pathogenesis and the implementation of rationally designed therapies based on these advances, advanced KS is mostly an incurable disease and many of the most promising new therapies continue to have major roadblocks and implementation problems in the setting of ART. We have shown that 1) KSHV lytic genes; and particularly the vGPCR oncogene can induce- PDGF mediated activation of PDGFRA and that this is the most prominently activated RTK in AIDS-KS and it is an oncogenic driver and a therapeutic target in KS. 2) We identified PDGFRA (+) mesenchymal stem cells as KS progenitors; and PDGFRA, as an enabler of KSHV oncogenesis in an angiogenic KS like environment and we developed of a new KSHV infection-to-tumorigenesis system that allows to dissect the effect of the angiogenic microenvironment and the contribution of viral and host mechanisms to oncogenesis 3) We found that the ability of the virus to regulate the oxygen sensing machinery allowed the virus to coopt the hypoxia-regulated alternative translation initiation machinery eIF4EH activated by HIF2a and mediated by eIF4E2 alternative cap-binding. This was essential for KSHV replication, for escaping the viral shut-off and for PDGFRA driven pathogenesis in MSCs. The importance of this discovery is that through its regulation of the oxygen sensing machinery the virus access to translation initiation plasticity, defined as the ability for KSHV to alternatively initiate protein synthesis using both the initiation complex eIF4E bearing a cap-binding regulated by the PI3K- AKT-mTOR -HIF1a (eIF4E1 cap-binding) axis or the eIF4EH (eIF4E2 cap-binding) regulated by the HIF2a. We hypothesize that this provides the virus with several adaptive advantages that we will study: 1) Allows the virus to maximize replication in different oxygen levels corresponding to variety of tissues and pathophysiological conditions and it may allow the virus to bypass the stress and innate immunity-related kinases targeting eIF2a inhibition 2) It may be employed by viral oncogenes such as vGPCR and/or by its host-cell signaling mediators such as PDGFRA for proliferation and the induction of direct and paracrine oncogenesis 3) Could allow the transformed host cell to be plastic and adaptive in the context of AIDS-KS therapies targeting PDGFRA such as Imatinib, which are known to target the PDGFRA-AKT-mTOR-E1-HIF1a pathway. We will employ the MSC based de novo oncogenesis to tumorigenesis models, an induction reactivation model and two natural infections systems and AIDS-KS samples from different repositories to test these hypotheses. Aim 1: Study how KSHV regulation of the oxygen sensing machinery (O2SM) leading to HIF2a activation of translational initiation by eIF4EH contributes to KSHV replication and innate immunity evasion. Aim 2: Study mechanisms whereby KSHV regulation of the oxygen sensing machinery leading to HIF2a activation of translational initiation by eIF4EH contributes to KSHV oncogenesis in mouse MSC and human MSCs. Aim 3: Role of translation initiation plasticity in mediating resistance to PDGFRA targeted therapies.

尽管我们了解KSHV的发病机制和实施合理设计的治疗， 基于这些进展，晚期KS大多是一种不治之症，许多最有前途的新疗法， 治疗仍然有主要的障碍和实施问题的设置艺术。我们已经表明， 1）KSHV裂解基因;特别是vGPCR癌基因可以诱导- PDGF介导的活化， PDGFRA是AIDS-KS中最显著的激活RTK，它是一种致癌驱动因子， KS的治疗靶点。2)我们鉴定PDGFRA（+）间充质干细胞为KS祖细胞; PDGFRA作为KSHV在血管生成KS样环境中肿瘤发生的促进因子，我们开发了一种 新的KSHV感染到肿瘤发生系统，允许解剖血管生成的影响， 微环境以及病毒和宿主机制对肿瘤发生的贡献3）我们发现， 调节氧感受机制的病毒， 翻译起始机制eIF 4 EH由HIF 2a激活并由eIF 4 E2替代帽结合介导。这 对于KSHV复制、逃避病毒关闭和PDGFRA驱动的MSC发病机制是必需的。 这一发现的重要性在于，通过它对氧传感机制的调节， 病毒获得翻译起始可塑性，定义为KSHV交替启动 蛋白质合成使用起始复合物eIF 4 E，其具有由PI 3 K调节的帽结合， AKT-mTOR -HIF 1a（eIF 4 E1帽结合）轴或由HIF 2a调节的eIF 4 EH（eIF 4 E2帽结合）。 我们假设，这为病毒提供了几个我们将研究的适应性优势：1）允许病毒在宿主细胞中传播。 病毒最大限度地复制在不同的氧气水平相应的各种组织和病理生理 它可能允许病毒绕过应激和靶向eIF 2a的先天免疫相关激酶 2）它可以被病毒致癌基因如vGPCR和/或其宿主细胞信号传导介质所利用 如PDGFRA的增殖和诱导直接和旁分泌肿瘤发生3）可以允许 转化的宿主细胞在靶向PDGFRA的AIDS-KS疗法中具有可塑性和适应性，例如 伊马替尼，已知可靶向PDGFRA-AKT-mTOR-E1-HIF 1a途径。我们将雇用MSC 基于从头肿瘤发生到肿瘤发生模型，诱导再激活模型和两种自然感染 系统和AIDS-KS样本从不同的存储库来测试这些假设。目标1：研究KSHV如何 氧传感机制（O2 SM）的调节导致HIF 2a激活翻译起始， eIF 4 EH有助于KSHV复制和先天免疫逃避。目的2：研究KSHV的机制 通过eIF 4 EH调节氧敏感机制导致HIF 2a激活翻译起始 在小鼠MSC和人MSC中的KSHV肿瘤发生中起作用。目的3：翻译起始可塑性的作用 介导PDGFRA靶向治疗的耐药性。