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：
8595304
负责人：
John Nicholas
金额：
$ 20.51万
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/8595304
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) 指定白细胞介素 6 的同源物 vIL-6，其与 HHV-8 相关的卡波西肉瘤、原发性渗出性淋巴瘤 (PEL) 的发生和进展有关和多中心卡斯尔曼病 (MCD)。我们已经确定，在 PEL 细胞中，vIL-6 在潜伏期的表达水平较低，但具有功能性； vIL-6 在这种情况下支持细胞生长和存活，并且这些功能主要由位于内质网 (ER) 中的 vIL-6 在细胞内介导。因此，vIL-6 的内分泌、严格自分泌信号可能是 PEL 疾病代表了疾病发病机制中细胞因子活性的独特模式。 vIL-6 在 PEL 细胞中的这种活性的机制尚不清楚，但我们已经确定了 vIL-6 与一种新蛋白质维生素 K 环氧化物还原酶复合物亚基 1 变体 2 (VKORC1v2) 的功能上重要的相互作用，并且还发现最近确定 IL-6 信号转导器 gp130 对于 PEL 细胞的持续生长至关重要。此外，我们还确定了 VKORC1v2 与硫氧还蛋白还原酶样蛋白 1 (TMX1)、蛋白二硫键异构酶 A6/P5 (PDI-A6) 和组织蛋白酶 D (catD) 的相互作用，这表明 VKORC1v2 与 vIL-6 折叠和/或相关的可能功能或 vIL-6 通过 VKORC1v2 相互作用对 ER 应激反应或 catD 处理和相关调节的影响促增殖和凋亡信号传导。在此 R21 申请中，我们建议鉴定和测试 PEL 抑制肽和 vIL-6:VKORC1v2 相互作用和功能性 vIL-6:gp130 复合的小分子抑制剂；我们还将评估经过验证的抑制剂对 VKORC1v2 与其新识别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 vIL-6 与 VKORC1v2 和 gp130 相互作用的功能表征，并提出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。该项目对于未来开发针对这种疾病以及其他 HHV-8 相关恶性肿瘤的药物疗法具有重大意义，其中 vIL-6 可能在其中发挥关键作用。