Kaposi's Sarcoma-associated Herpesvirus Mimics of Cellular microRNAs

卡波西肉瘤相关疱疹病毒的细胞 microRNA 模拟物

基本信息

批准号：
8732118
负责人：
Eva Henriette Gottwein
金额：
$ 32.06万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8732118
关键词：
Acquired Immunodeficiency Syndrome Actins Address Adherens Junction Adhesions Affect B Cell Proliferation B-Cell Lymphomas B-Lymphocytes Binding Sites Biology Blood Vessels Cell Line Cell-Cell Adhesion Cell-Matrix Junction Cells Cellular Morphology Code Collaborations Cytoskeleton Data Disease Employee Strikes Endothelial Cells Gene Expression Gene Expression Profile Goals Growth Factor Hallmark Cell Herpesviridae Infections Human Human Herpesvirus 8 Image Individual Infection Kaposi Sarcoma Laboratories Lentivirus Vector Link Maintenance Malignant Neoplasms Mediating Mediator of activation protein Messenger RNA MicroRNAs Neoplasms Oncogenic PTEN gene Pathogenesis Play Property Proteins Publishing Qualifying Reagent Regulation Repression Role Sequence Homology Signal Pathway Signal Transduction Staging Structure Testing Untranslated RNA Validation Viral Viral Oncogene Virus Work angiogenesis base cell growth regulation cell transformation cellular targeting infected B cell mimicry mutant myo-inositol-1 (or 4)-monophosphatase novel primary effusion lymphoma public health relevance research study response tumorigenesis

项目摘要

Summary Kaposi's Sarcoma-associated herpesvirus (KSHV) causes the AIDS-associated malignancies Kaposi's Sarcoma (KS), and primary effusion lymphoma (PEL), resulting from KSHV-infection of endothelial cells (ECs) and B cells, respectively. KSHV encodes a set of microRNAs (miRNAs) with largely unknown significance to KSHV-associated disease. We have demonstrated that the KSHV miRNAs miR-K11, miR-K3 and miR-K10a repress mRNA targets of cellular miR-155, miR-23 and miR-142-3p, respectively. The goal of this proposal is to understand the potential significance of this mimicry to the pathogenesis of PEL and KS. Our preliminary data suggest that miR-K3 and miR-K11 together are essential for the survival of PEL-derived cell lines and synergize to target repressors of survival signaling and B-cell proliferation. In Aim 1, we therefore propose to phenotypically and mechanistically characterize the requirement for miR-K3 and miR-K11 for B-cell transformation by KSHV. Aims 2 and 3 address functions of miR-K10a. miR-K10a is expressed from the Kaposin A coding sequence, which has known oncogenic properties. Our preliminary experiments suggest that miR-K10a is the actual mediator of this transforming activity. In Aim 2, we therefore propose to further characterize the oncogenic properties of miR-K10a and to elucidate the underlying mechanism, based on already identified candidate targets with roles in transformation. Our analysis of miR-K10a targets and preliminary experiments suggest that miR-K10a functions in ECs to disrupt adherens junctions (AJs) and to remodel the actin cytoskeleton. miR-K10a expression caused a striking elongation of ECs, reminiscent of the KSHV-infected infected spindle cells that are the hallmark of KS. Because AJs and the linked actin cytoskeleton play important roles in vascular integrity, angiogenesis and the maintenance of EC quiescence by antagonizing growth factor signaling, their deregulation by miR-K10a may directly impact KS pathogenesis. In Aim 3, we therefore propose to phenotypically and mechanistically characterize how miR-K10a affects these structures and associated signaling pathways. Together, the proposed experiments will identify key roles of these KSHV miRNAs in KSHV oncogenesis.

概括 Kaposi的肉瘤相关疱疹病毒（KSHV）导致与艾滋病相关的恶性肿瘤Kaposi's 肉瘤（KS）和原发性淋巴瘤（PEL），由内皮细胞的KSHV感染（EC）产生和B细胞分别。 KSHV编码一组microRNA（miRNA），对 KSHV相关疾病。我们已经证明了KSHV miRNAS miR-K11，miR-k3和miR-k10a 分别抑制细胞miR-155，miR-23和miR-142-3p的mRNA靶标。该提议的目的是了解这种模仿对PEL和KS发病机理的潜在意义。我们的初步数据表明，miR-k3和miR-k11一起对于pel衍生的细胞系的存活至关重要与生存信号传导和B细胞增殖的目标阻遏物协同作用。在AIM 1中，我们建议表型和机械地表征miR-k3和miR-k11对B细胞的需求 KSHV的转换。目标2和3地址miR-k10a的功能。 mir-k10a从 kaposin A编码序列，该序列已知，已知。我们的初步实验表明 miR-k10a是这种转化活性的实际中介。因此，在AIM 2中，我们建议进一步表征miR-k10a的致癌特性并阐明基于基础机制已经确定了具有转换角色的候选目标。我们对miR-k10a目标的分析和初步实验表明，miR-k10a在EC中起作用，以破坏粘附连接（AJS）和to 重塑肌动蛋白细胞骨架。 miR-k10a表达引起了EC的惊人伸长，让人联想到 KSHV感染的受感染的纺锤体是KS的标志。因为AJ和链接的肌动蛋白细胞骨架在血管完整性，血管生成和维持EC静止的重要作用拮抗生长因子信号传导，对miR-K10a的放松管制可能直接影响KS发病机理。在 AIM 3，因此，我们建议通过表型和机械理论地表征miR-k10a如何影响这些结构和相关的信号通路。提出的实验将共同确定这些KSHV miRNA在KSHV肿瘤发生中。