Inhibitory targeting of HHV-8 vIL-6-related interactions.

HHV-8 vIL-6 相关相互作用的抑制性靶向。

基本信息

批准号：
8467210
负责人：
John Nicholas
金额：
$ 17.62万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8467210
关键词：
Address Apoptotic Autocrine Communication B lymphoid malignancy Binding Biological Assay Biology Cathepsins Cell Proliferation Cell Survival Cells Clinical Trials Complex Data Development Disease Dose Endoplasmic Reticulum FDA approved Future Genes Growth Homologous Gene Human Herpesvirus 8 In Vitro Interleukin-6 Kaposi Sarcoma Libraries Ligands Lytic Malignant Neoplasms Mediating Molecular Multicentric Angiofollicular Lymphoid Hyperplasia Oncogenes Paracrine Communication Pathogenesis Pathway interactions Peptides Pharmaceutical Preparations Play Process Protein Disulfide Isomerase Proteins RNA Splicing Regulation Relative (related person)Role Signal Transduction Site Specific qualifier value Structure Supporting Cell Testing Therapeutic Tumor Suppressor Proteins Variant Viral Viral Physiology Viral Proteins Virus Virus Inhibitors Work angiogenesis autocrine base biological adaptation to stress cell growth cellular targeting chemokine cytokine cytokine receptor gp130 drug development endoplasmic reticulum stress in vivo inhibitor/antagonist mimetics mimicry novel primary effusion lymphoma protein aminoacid sequence public health relevance receptor screening small molecule therapy development thioredoxin reductase tumor virus host interaction vitamin K epoxide reductase

项目摘要

DESCRIPTION (provided by applicant): Human herpesvirus 8 (HHV-8) specifies a homologue of interleukin-6, vIL-6, which is implicated in the development and progression of HHV-8-associated Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). We have determined that in PEL cells vIL-6 is expressed at low but functional levels during latency; vIL-6 in this setting supports cell growth and survival, and these functions are mediated predominantly intracellularly by vIL-6 localized in the endoplasmic reticulum (ER). Thus, intracrine, strictly autocrine signaling by vIL-6 is likely to be an important contributor to PEL disease and represents a unique mode of cytokine activity in disease pathogenesis. The mechanisms underlying this activity of vIL-6 in PEL cells is not understood, but we have identified a functionally important interaction of vIL-6 with a novel protein, vitamin K epoxide reductase complex subunit 1 variant-2 (VKORC1v2), and also have recently determined that the IL-6 signal transducer, gp130, is essential for sustained growth of PEL cells. Additionally, we have identified interactions of VKORC1v2 with thioredoxin reductase-like protein 1 (TMX1), protein disulfide isomerase A6/P5 (PDI-A6) and cathepsin D (catD) that suggest possible functions of VKORC1v2 related to vIL-6 folding and/or influence of vIL-6, via VKORC1v2 interaction, on ER stress responses or on catD processing and associated regulation of pro-proliferative and apoptotic signaling. In this R21 application, we propose to identify and test in respect of PEL inhibition peptide and small molecule inhibitors of vIL- 6:VKORC1v2 interaction and functional vIL-6:gp130 complexing; we will also assess the effects of validated inhibitors on functions predicted from interaction of VKORC1v2 with its newly identified cellular interaction partners. The work therefore extends our functional characterization of vIL-6 interactions with VKORC1v2 and gp130 in the context of PEL and addresses molecular strategies to target these biologically important virus- host interactions. The project has substantial significance to the future development of drug-based therapies for this and possibly other HHV-8-associated malignancies in which vIL-6 is likely to play a critical role.

描述（由申请人提供）：人类疱疹病毒8（HHV-8）指定了Interleukin-6，VIL-6的同源物，这与HHV-8相关的Kaposi的Kaposi的Sarcoma的开发和进展有关，这与初级积液淋巴瘤（PEL）（PEL）和多中心Castleman的病（MCD）有关。我们已经确定，在PEL细胞中，VIL-6在潜伏期期间以低但功能水平表示。 VIL-6在这种情况下支持细胞的生长和生存，这些功能由内质网（ER）中定位的VIL-6主要在细胞内介导。因此，内在的，vil-6严格的自分泌信号传导可能是重要的贡献者 PEL病，代表了疾病发病机理中细胞因子活性的独特模式。尚不了解VIL-6在PEL细胞中这种活性的机制，但是我们已经确定了VIL-6与新型蛋白质，维生素K氧化物还原酶复杂的亚基1变体-2（VKORC1V2）的功能重要相互作用，并且最近也确定了IL-6信号传递器，GP130的生长。此外，我们已经确定了VKORC1V2与硫氧还蛋白还原酶样蛋白1（TMX1），蛋白质二硫化物异构酶A6/P5（PDI-A6）和组织蛋白酶d（CATD）的相互作用，这些相互作用暗示了与VKORC1V2的可能功能与VIL-6折叠和/或影响VKOR-6的相互作用，从关于CATD处理和相关的促生殖和凋亡信号的调节。在此R21应用中，我们建议在VIL-6：VKORC1V2相互作用和功能性VIL-6：GP130复合物的pel抑制肽和小分子抑制剂方面识别和测试；我们还将评估经过验证的抑制剂对VKORC1V2与其新鉴定的细胞相互作用伙伴相互作用预测的功能的影响。因此，这项工作扩展了我们在PEL背景下与VKORC1V2和GP130的VIL-6相互作用的功能表征，并解决了针对这些生物学上重要的病毒宿主相互作用的分子策略。该项目对于该项目的未来开发基于药物的疗法的发展具有重要意义，该项目在该项目中以及其他与HHV-8相关的恶性肿瘤中可能发挥关键作用。