Anti-nucleolin aptamer AS1411: Applications in Kaposi's Sarcoma Associated Herpes Virus (KSHV) biology

抗核仁素适体 AS1411：在卡波西肉瘤相关疱疹病毒 (KSHV) 生物学中的应用

基本信息

批准号：
10619191
负责人：
Neelam Sharma-Walia
金额：
$ 21.88万
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：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10619191
关键词：
Angiogenesis Inhibitors Angiogenic Factor Antibodies Antiviral Agents B-Cell Lymphomas B-Cell NonHodgkins Lymphoma Biogenesis Biology Blood Vessels Cell Death Induction Cell Line Cell Survival Cells Cellular Metabolic Process Chemicals Cyclophosphamide DNA Development Diagnosis Dose Doxorubicin Endothelial Cells Endothelium Environment Etiology Exhibits Family G-Quartets Gene Expression Gene Proteins Genes Growth Factor HIV HIV therapy Herpesviridae Herpesviridae Infections Herpesvirus 1 Human Human Herpesvirus 8 Human poliovirus Immunocompromised Host Incubated Infection Inflammatory Integration Host Factors Interleukin-6 Intervention Kaposi Sarcoma Knowledge Lesion Life Cycle Stages Link Lymphangiogenesis Lymphoid Tissue Lymphoma cell Lytic Lytic Phase Maintenance Malignant Neoplasms Mediating Messenger RNA Metabolic Pathway Morbidity - disease rate Multicentric Angiofollicular Lymphoid Hyperplasia Oligonucleotides Paracrine Communication Pathogenesis Pathway interactions Patients Pharmacy (field)Phase Post-Transcriptional Regulation Prednisone Prognosis Proliferating Proteins RNA-Binding Proteins Respiratory syncytial virus Ribosomes Role Safety Serious Adverse Event Shapes Signal Transduction Skin Kaposi&apos s Sarcoma Skin Tissue Syndrome Telomerase Testing Therapeutic Transcription Coactivator Transcriptional Regulation Translational Regulation Vascular Endothelial Cell Vincristine Viral Viral Cancer Viral Genes Viral Regulatory Proteins Virion angiogenesis anti-cancer antiretroviral therapy aptamer autocrine body cavity cancer therapy chemotherapy chromatin remodeling co-infection cytokine effusion gammaherpesvirus hematopoietic tissue histone modification in vitro Model in vivo Model latency-associated nuclear antigen latency-associated protein member mortality novel nucleolin primary effusion lymphoma programs rare cancer skin lesion theranostics tumor tumorigenic uptake

Angiogenesis Inhibitors Angiogenic Factor Antibodies Antiviral Agents B-Cell Lymphomas B-Cell NonHodgkins Lymphoma Biogenesis Biology Blood Vessels Cell Death Induction Cell Line Cell Survival Cells Cellular Metabolic Process Chemicals Cyclophosphamide DNA Development Diagnosis Dose Doxorubicin Endothelial Cells Endothelium Environment Etiology Exhibits Family G-Quartets Gene Expression Gene Proteins Genes Growth Factor HIV HIV therapy Herpesviridae Herpesviridae Infections Herpesvirus 1 Human Human Herpesvirus 8 Human poliovirus Immunocompromised Host Incubated Infection Inflammatory Integration Host Factors Interleukin-6 Intervention Kaposi Sarcoma Knowledge Lesion Life Cycle Stages Link Lymphangiogenesis Lymphoid Tissue Lymphoma cell Lytic Lytic Phase Maintenance Malignant Neoplasms Mediating Messenger RNA Metabolic Pathway Morbidity - disease rate Multicentric Angiofollicular Lymphoid Hyperplasia Oligonucleotides Paracrine Communication Pathogenesis Pathway interactions Patients Pharmacy (field)Phase Post-Transcriptional Regulation Prednisone Prognosis Proliferating Proteins RNA-Binding Proteins Respiratory syncytial virus Ribosomes Role Safety Serious Adverse Event Shapes Signal Transduction Skin Kaposi&apos s Sarcoma Skin Tissue Syndrome Telomerase Testing Therapeutic Transcription Coactivator Transcriptional Regulation Translational Regulation Vascular Endothelial Cell Vincristine Viral Viral Cancer Viral Genes Viral Regulatory Proteins Virion angiogenesis anti-cancer antiretroviral therapy aptamer autocrine body cavity cancer therapy chemotherapy chromatin remodeling co-infection cytokine effusion gammaherpesvirus hematopoietic tissue histone modification in vitro Model in vivo Model latency-associated nuclear antigen latency-associated protein member mortality novel nucleolin primary effusion lymphoma programs rare cancer skin lesion theranostics tumor tumorigenic uptake

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项目摘要

Kaposi’s sarcoma-associated herpesvirus (KSHV), a member of the human γ-herpesvirus family is also termed as human herpesvirus type 8 (HHV-8). KSHV is an etiological agent of an endothelial tumor called Kaposi’s sarcoma (KS) and a highly aggressive lymphoproliferative B cell lymphoma called primary effusion lymphoma (PEL). KS is the most common vascular malignancy causing high morbidity and mortality in HIV-infected patients. PEL is a rare tumor of hematopoietic and lymphoid tissues and is associated with a poor prognosis. PEL cases have been dramatically reduced in the US since the widespread use of combined antiretroviral therapy (cART) but KSHV still causes significant mortality in the developing world. There is a critical need in KSHV targeting specific antiviral drugs, which are very well tolerated with no severe adverse events for immunocompromised patients with KSHV associated malignancies. KSHV exhibits two distinct phases in its life cycle. During latency, a minimal number of latency genes such as vFLIP (ORF71), vCyclin (ORF72), latency-associated nuclear antigen-1 (LANA-1; ORF73), and Kaposin are expressed. By contrast, during the lytic phase, KSHV expresses a wide array of immediate-early (IE), delayed-early (DE), and late genes; undergo active replication and produce virion progeny. KSHV has been shown to utilize multiple host growth factors, cytokines, angiogenic factors, and cell signaling and metabolism-related proteins for creating a beneficial environment for its replication, survival, and latency. Our exciting studies discovered that: 1) KS skin lesions express remarkably robust expression of nucleolin compared to healthy skin tissue; 2) KSHV de novo infection in primary endothelial cells induced a high level of nucleolin and phospho-nucleolin, and more importantly, 3) Incubation of KSHV infected cells with G- quadruplex forming anti-nucleolin aptamer AS1411 reduced KSHV latent (ORF73) and increased lytic (ORF50) gene expression and we obtained similar results in nucleolin silenced KSHV infected PEL cells. 4) AS1411 treatment was efficacious in inducing cell death in KSHV infected PEL cell lines. Based on our preliminary results, we hypothesize that KSHV induces host factor nucleolin to support its latency and life cycle and targeting nucleolin with AS1411 would have therapeutic potential in KSHV associated malignancies. To test this hypothesis, we have formulated two specific aims in which we will 1) To determine the regulatory mechanisms of nucleolin expression upon KSHV infection and its role in KSHV latency, and 2) To evaluate the chemotherapeutic potential of using AS1411 to treat KS and PEL. Our studies are significant and will have a positive impact by advancing the unexplored and novel targeted theranostic field of aptamers in KSHV biology and understanding their antiviral and anticancer potential can also be applied to other viral malignancies.

Kaposi的肉瘤相关疱疹病毒（KSHV），也称为人γ-HERPESVIRUS家族的成员作为人类疱疹病毒8型（HHV-8）。 KSHV是一种名为Kaposi的内皮肿瘤的病因学药肉瘤（KS）和高度侵袭性的淋巴增生B细胞淋巴瘤称为一级积液淋巴瘤（PEL）。 KS是最常见的血管恶性肿瘤，导致HIV感染患者的发病率高和死亡率。 PEL是造血和淋巴组织的罕见肿瘤，与预后不良有关。 PEL病例自从宽度使用抗逆转录病毒疗法（CART）以来，美国已经大大降低了但是KSHV在发展中国家仍会引起重大死亡率。 KSHV定位有急需的需求特异性抗病毒药物的耐受性很好具有KSHV相关的恶性肿瘤的患者。 KSHV在其生命周期中表现出两个不同的阶段。在延迟期间，诸如VFLIP（ORF71），Vcyclin（ORF72），延迟相关的核的延迟基因数量最少抗原1（LANA-1； ORF73）和KAPOSIN表示。相比之下，在裂解阶段，KSHV表示众多（IE），延迟（de）和晚期基因的广泛（IE）；进行主动复制并产生病毒体后代。 KSHV已被证明使用了多种宿主生长因子，细胞因子，血管生成因子和细胞信号传导和与代谢相关的蛋白质，以创造有益的环境，以使其复制，生存，和延迟。我们令人兴奋的研究发现：1）KS皮肤病变表达了非常强大的表达与健康的皮肤组织相比，核酸素蛋白； 2）原代内皮细胞中的kshv de从头感染诱导高核醇蛋白和磷酸核苷的水平，更重要的是，3）与G-一起孵育KSHV感染细胞四链体形成抗核蛋白APATMER AS1411减少了KSHV潜伏（ORF73），并增加裂解（ORF50）基因表达，我们在核仁素沉默的KSHV感染PEL细胞中获得了相似的结果。 4）AS1411 在KSHV感染的PEL细胞系中，治疗在诱导的细胞死亡中有效。根据我们的初步结果我们假设KSHV会影响宿主因子核苷，以支持其潜伏期，生命周期和靶向具有AS1411的核苷在KSHV相关的恶性肿瘤中具有治疗潜力。测试这个假设，我们提出了两个具体目的，其中我们将1）确定调节机制 KSHV感染时核苷表达及其在KSHV潜伏期中的作用，以及2）使用AS1411治疗KS和PEL的化学治疗潜力。我们的研究很重要，将有通过推进KSHV生物学中适体的意外靶向热场的积极影响并且了解其抗病毒和抗癌潜力也可以应用于其他病毒性恶性肿瘤。