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：
9206142
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/9206142
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 Regulation Goals Growth Factor Hallmark Cell Herpesviridae Infections Human Human Herpesvirus 8 Image Individual Infection Inositol Kaposi Sarcoma Laboratories Lentivirus Vector Link Maintenance Malignant Neoplasms Mediating Mediator of activation protein Messenger RNA MicroRNAs Neoplasms Oncogenic PTEN gene Pathogenesis Phenotype Phosphoric Monoester Hydrolases Play Primary Infection Property Proteins Publishing Reagent Regulation Repression Role Sequence Homology Signal Pathway Signal Transduction Spindle Cell Sarcomas Structure Testing Untranslated RNA Validation Viral Viral Oncogene Virus Work angiogenesis base cell growth regulation cell transformation cellular targeting experimental study infected B cell mimicry mutant novel primary effusion lymphoma public health relevance response transcriptome tumorigenesis

项目摘要

DESCRIPTION: 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.

描述：Kaposi的肉瘤相关疱疹病毒（KSHV）引起了与内皮细胞（ECS）和B细胞的KSHV感染有关的艾滋病相关的恶性肿瘤Kaposi的肉瘤（KS）和一级积液淋巴瘤（PEL）。 KSHV编码一组对KSHV相关疾病的意义的microRNA（miRNA）。我们已经证明，分别分别是细胞miR-155，miR-155，miR-23和miR-142-3p的KSHV miRNA MiR-K11，miR-K3和miR-k10a抑制mRNA靶标。该提案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在一起对于pel衍生的细胞系的存活和协同靶向生存信号传导和B细胞增殖的靶向器至关重要。因此，在AIM 1中，我们建议通过表型和机械理论地表征MiR-K3和miR-K11对KSHV的B细胞转化的需求。目标2和3地址miR-k10a的功能。 miR-k10a从kaposin A编码序列表示，该序列已知，该序列已知。我们的初步实验表明，miR-k10a是这种转化活性的实际介体。因此，在AIM 2中，我们建议进一步表征miR-K10a的致癌特性，并基于已经确定的具有在转化中作用的候选目标，以阐明基本机制。我们对miR-k10a靶标和初步实验的分析表明，miR-k10a在EC中起作用，以破坏粘附连接（AJS）并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细胞，这是KS的标志。由于AJ和链接的肌动蛋白细胞骨架在血管完整性，血管生成和通过拮抗生长因子信号传导的维持中起重要作用，因此它们对miR-K10A的放松管制可能直接影响KS发病机理。因此，在AIM 3中，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。共同提出的实验将确定这些KSHV miRNA在KSHV肿瘤发生中的关键作用。