Lipoxins and aspirin triggered lipoxins in KSHV latency and pathogenesis

脂氧素和阿司匹林在 KSHV 潜伏期和发病机制中触发脂氧素

基本信息

批准号：
9352789
负责人：
Neelam Sharma-Walia
金额：
$ 35.69万
依托单位：
ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9352789
关键词：
Acetylation Adverse effects Angiogenic Factor Anti-Inflammatory Agents Anti-inflammatory Antiviral Agents Arachidonate 5-Lipoxygenase Arachidonic Acids Ascites Aspirin Attenuated B-Cell Lymphomas B-Lymphocytes Biology Cardiovascular system Cell Death Cell Line Cell Proliferation Cell Survival Cell model Cells Chromatin Clinical Management DNA biosynthesis Dinoprostone Dose Drug resistance Endothelial Cells Epigenetic Process Etiology FPR2 gene FRAP1 gene Gene Expression Genetic Transcription Goals HIV HIV-1 Herpesviridae Infections Human Human Herpesvirus 8 Immune response Immunocompromised Host In Vitro Inflammatory Kaposi Sarcoma Knowledge Lead Lesion Life Cycle Stages Link Lipids Lipoxin Receptors Lipoxins Lipoxygenase Lipoxygenase Inhibitors Lytic Lytic Phase MAPK3 gene Malignant Neoplasms Mediating Morbidity - disease rate Multicentric Angiofollicular Lymphoid Hyperplasia NOD/SCID mouse PTGS2 gene Pathogenesis Pathway interactions Patients Persons Phosphotransferases Prevention Protein Tyrosine Kinase Proto-Oncogene Proteins c-akt Regulation Resolution Role Scheme Second Primary Cancers Signal Pathway Signal Transduction Testing Therapeutic Time Tumorigenicity Viral Viral Genome Viral Load result Virus Latency analog base cancer cell cell immortalization cohesin cyclooxygenase 2 cytokine cytotoxic design effective therapy efficacy testing effusion immortalized cell in vivo innovation latent gene expression lipoxin A4 lipoxin B4 mortality mouse model novel primary effusion lymphoma public health relevance receptor small molecule targeted treatment transcription factor treatment strategy tumor tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), B cell lymphoproliferative primary effusion lymphoma (PEL) and multicentric Castleman's disease. KSHV latent viral genome, latent viral gene expression, deregulated secretion of cytokines, and aggressive angiogenic factors are critical for KS, PEL and MCD. Current treatments for KS and PEL rely on less effective cytotoxic systemic chemotherapeutics developed for non-virus-associated cancers that target DNA replication of all dividing cells. These treatment approaches have multiple myelosuppressive side effects, especially in immunocompromised patients. Hence, there is a critical need to design safe anti-viral therapies that simultaneously target tumors and eradicate viral load. Our long-term goal is to evaluate the role of arachidonic acid pathways of the host in KSHV biology. Our exciting studies discovered that 1) KSHV infection, aside from hijacking proinflammatory cyclyoxygenase-2 and 5-lipoxygenase pathways, significantly reduces the secretion of anti-inflammatory lipoxin LXA4; 2) KSHV infected cells and human KS lesion cells express lipoxin receptor ALXR, and more importantly 3) Incubation of KSHV infected cells with stable small molecule analogs of LXA4s and aspirin triggered lipoxins significantly downregulate KSHV's latent gene expression and decreases the infected cell survival. From these novel observations, we hypothesize that anti-inflammatory lipoxins mediate adverse effects on KSHV latency while at the same time, KSHV strategically reduces lipoxin secretion to maintain its latency and the survival of latently infected cells. To test this hypothesis, we have formulated three specific aim in which we will decipher the links between lipoxins, KSHV life cycle, and pathogenesis. Since current prevention and treatment options for KS and PEL are inadequate, the studies to evaluate the role of less explored lipoxins, aspirin triggered lipoxins, and their targetable receptor ALXR in KSHV's latency and pathogenesis are expected to reveal new and innovative therapeutic approaches. Our studies are significant and will have a positive impact by advancing the unexplored field of anti-inflammatory lipoxins in KSHV biology, and understanding their antiviral and anticancer potential can also be applied to other viral malignancies.

描述（由适用提供）：Kaposi与肉瘤相关的疱疹病毒（KSHV）是Kaposi的肉瘤（KS），B细胞淋巴细胞增生性原发性淋巴瘤（PEL）和多中心Castleman病。 KSHV潜在病毒基因组，潜在病毒基因表达，细胞因子的分泌放松管制以及侵袭性的血管生成因子对于KS，PEL和MCD至关重要。当前对KS和PEL的治疗依赖于针对针对所有分裂细胞的DNA复制的非病毒相关癌症开发的细胞毒性系统化学治疗剂。这些治疗方法具有多种骨髓抑制副作用，尤其是在免疫功能低下的患者中。因此，至关重要的是设计仅针对肿瘤和放射性病毒负荷的安全抗病毒疗法。我们的长期目标是评估宿主在KSHV生物学中的蛛网膜化途径的作用。我们的激动人心的研究发现，除了劫持促炎性环氧酶-2和5-脂氧合酶途径外，KSHV感染显着降低了抗炎脂肪毒素LXA4的分泌； 2）KSHV感染的细胞和人KS病变细胞表达脂氧蛋白受体ALXR，更重要的是3）与LXA4S的稳定的小分子类似物一起孵育KSHV感染细胞和阿司匹林触发的Lipoxins显着下调了KSHV的潜在基因表达并降低了感染的细胞存活。从这些新颖的观察结果中，我们假设抗炎脂蛋白培养基对KSHV潜伏期的不利影响，同时，KSHV策略性地减少了脂氧蛋白的分泌，以维持其潜伏期和潜在感染细胞的存活。为了检验这一假设，我们提出了三个特定的目的，其中我们将破译脂毒素，KSHV生命周期和发病机理之间的联系。由于当前的KS和PEL治疗方案不足，因此评估较少探索的脂毒素，阿司匹林触发的脂毒素的作用以及其在KSHV潜伏期中的可靶向受体ALXR的研究预计有望揭示新的和创新的治疗方法。我们的研究很重要，并且通过推进KSHV生物学中抗炎脂蛋白的意外领域的意外影响，并且了解其抗病毒药和抗癌潜力也可以应用于其他病毒性恶性肿瘤。