Lipoxins and aspirin triggered lipoxins in KSHV latency and pathogenesis

 描述（由申请方提供）：卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤（KS）、B细胞淋巴增生性原发性渗出性淋巴瘤（PEL）和多中心Castleman病的病原体。KSHV潜伏病毒基因组、潜伏病毒基因表达、细胞因子分泌失调和侵袭性血管生成因子是KS、PEL和MCD的关键。目前KS和PEL的治疗依赖于针对所有分裂细胞的DNA复制的非病毒相关癌症开发的不太有效的细胞毒性全身化疗药物。这些治疗方法具有多种骨髓抑制副作用，特别是在免疫功能低下的患者中。因此，迫切需要设计同时靶向肿瘤和根除病毒载量的安全抗病毒疗法。我们的长期目标是评估花生四烯酸途径在KSHV生物学中的作用。我们激动人心的研究发现：1）KSHV感染，除了劫持促炎环氧化酶-2和5-脂氧合酶途径外，还显著减少抗炎脂氧素LXA 4的分泌; 2）KSHV感染细胞和人KS病变细胞表达脂氧素受体ALXR，更重要的是（3）将KSHV感染的细胞与稳定的LXA 4和阿司匹林的小分子类似物孵育，触发脂氧素显著下调KSHV的潜伏基因表达，降低了受感染细胞的存活率。从这些新的观察结果，我们假设抗炎脂氧素介导对KSHV潜伏期的不良影响，而同时，KSHV策略性地减少脂氧素分泌以维持其潜伏期和潜伏感染细胞的存活。为了验证这一假设，我们制定了三个具体的目标，我们将破译脂氧素，KSHV生命周期和发病机制之间的联系。由于目前KS和PEL的预防和治疗方案不足，因此评估较少探索的脂氧素、阿司匹林触发的脂氧素及其靶向受体ALXR在KSHV潜伏期和发病机制中的作用的研究有望揭示新的和创新的治疗方法。我们的研究意义重大，将通过推进KSHV生物学中抗炎脂氧素的未探索领域产生积极影响，并了解其抗病毒和抗癌潜力也可应用于其他病毒恶性肿瘤。

 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.