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

基本信息

批准号：
10524074
负责人：
Enrique A Mesri
金额：
$ 6.17万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10524074
关键词：
AIDS therapy Acquired Immunodeficiency Syndrome Affect Binding Bypass Cancer Etiology Cells Clinical Complex Development Disease Environment FRAP1 gene Feedback Genes Genetic HIV Human Human Herpesvirus 8 Hypoxia Imatinib In Vitro Infection Kaposi Sarcoma Lytic Mediating Mediator of activation protein Mesenchymal Stem Cells Modeling Molecular Mus Natural Immunity Oncogenes Oncogenic Outcome Oxygen PDGFRA gene Pathogenesis Pathway interactions Phosphotransferases Platelet-Derived Growth Factor Populations at Risk 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 base design global health in vivo Model insight novel therapeutics paracrine phenotypic biomarker progenitor rational design recruit repository targeted treatment therapeutic target therapy design tumor tumorigenesis

项目摘要

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 发病机制并实施合理设计的疗法基于这些进展，晚期 KS 大多是一种无法治愈的疾病，并且许多最有前途的新疾病在 ART 领域，各种疗法仍然存在重大障碍和实施问题。我们已经展示了 1) KSHV 裂解基因；尤其是 vGPCR 癌基因可以诱导 PDGF 介导的 PDGFRA 是 AIDS-KS 中最显着激活的 RTK，它是致癌驱动因素和 KS 的治疗目标。 2）我们鉴定PDGFRA（+）间充质干细胞为KS祖细胞；和 PDGFRA，作为 KSHV 肿瘤发生在血管生成 KS 样环境中的推动者，我们开发了新的 KSHV 感染到肿瘤发生系统，可以剖析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) 我们发现病毒调节氧传感机制使病毒能够选择缺氧调节的替代方案翻译起始机制 eIF4EH 由 HIF2a 激活并由 eIF4E2 替代帽结合介导。这对于 KSHV 复制、逃避病毒关闭以及 PDGFRA 驱动的 MSC 发病机制至关重要。这一发现的重要性在于，通过其对氧传感机制的调节，病毒获得翻译起始可塑性，定义为 KSHV 选择性起始的能力使用带有由 PI3K- 调节的帽结合的起始复合物 eIF4E 进行蛋白质合成 AKT-mTOR -HIF1a（eIF4E1 帽结合）轴或 eIF4EH（eIF4E2 帽结合）受 HIF2a 调节。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）允许病毒在与各种组织和病理生理学相对应的不同氧气水平下最大化复制它可能允许病毒绕过针对 eIF2a 的应激和先天免疫相关激酶抑制 2) 它可能被病毒癌基因（例如 vGPCR）和/或其宿主细胞信号传导介质所利用例如用于增殖和诱导直接和旁分泌肿瘤发生的 PDGFRA 3) 可以允许在针对 PDGFRA 的 AIDS-KS 疗法中，将宿主细胞转化为可塑性和适应性，例如伊马替尼，已知靶向 PDGFRA-AKT-mTOR-E1-HIF1a 通路。我们将聘请 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来自不同存储库的 AIDS-KS 样本来测试这些假设。目标 1：研究 KSHV 如何氧传感机制 (O2SM) 的调节导致 HIF2a 激活翻译起始 eIF4EH 有助于 KSHV 复制和先天免疫逃避。目标 2：研究 KSHV 的机制氧传感机制的调节导致 eIF4EH 激活 HIF2a 翻译起始有助于小鼠 MSC 和人类 MSC 中的 KSHV 肿瘤发生。目标 3：翻译起始可塑性的作用介导 PDGFRA 靶向治疗的耐药性。