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:
- 金额:$ 21.88万
- 依托单位:
- 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:
- 关键词:Angiogenesis InhibitorsAngiogenic FactorAntibodiesAntiviral AgentsB-Cell LymphomasB-Cell NonHodgkins LymphomaBiogenesisBiologyBlood VesselsCell Death InductionCell LineCell SurvivalCellsCellular Metabolic ProcessChemicalsCyclophosphamideDNADevelopmentDiagnosisDoseDoxorubicinEndothelial CellsEndotheliumEnvironmentEtiologyExhibitsFamilyG-QuartetsGene ExpressionGene ProteinsGenesGrowth FactorHIVHIV therapyHerpesviridaeHerpesviridae InfectionsHerpesvirus 1HumanHuman Herpesvirus 8Human poliovirusImmunocompromised HostIncubatedInfectionInflammatoryIntegration Host FactorsInterleukin-6InterventionKaposi SarcomaKnowledgeLesionLife Cycle StagesLinkLymphangiogenesisLymphoid TissueLymphoma cellLyticLytic PhaseMaintenanceMalignant NeoplasmsMediatingMessenger RNAMetabolic PathwayMorbidity - disease rateMulticentric Angiofollicular Lymphoid HyperplasiaOligonucleotidesParacrine CommunicationPathogenesisPathway interactionsPatientsPharmacy (field)PhasePost-Transcriptional RegulationPrednisonePrognosisProliferatingProteinsRNA-Binding ProteinsRespiratory syncytial virusRibosomesRoleSafetySerious Adverse EventShapesSignal TransductionSkin Kaposi&aposs SarcomaSkin TissueSyndromeTelomeraseTestingTherapeuticTranscription CoactivatorTranscriptional RegulationTranslational RegulationVascular Endothelial CellVincristineViralViral CancerViral GenesViral Regulatory ProteinsVirionangiogenesisanti-cancerantiretroviral therapyaptamerautocrinebody cavitycancer therapychemotherapychromatin remodelingco-infectioncytokineeffusiongammaherpesvirushematopoietic tissuehistone modificationin vitro Modelin vivo Modellatency-associated nuclear antigenlatency-associated proteinmembermortalitynovelnucleolinprimary effusion lymphomaprogramsrare cancerskin lesiontheranosticstumortumorigenicuptake
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.
卡波西肉瘤相关疱疹病毒(KSHV)是人类γ-疱疹病毒家族的一员
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Neelam Sharma-Walia其他文献
Neelam Sharma-Walia的其他文献
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{{ truncateString('Neelam Sharma-Walia', 18)}}的其他基金
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
- 批准号:
9751787 - 财政年份:2016
- 资助金额:
$ 21.88万 - 项目类别:
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
- 批准号:
9352789 - 财政年份:2016
- 资助金额:
$ 21.88万 - 项目类别:
Role of Cyclooxygenase-2 and PGE2 in KSHV pathogenesis
Cyclooxygenase-2 和 PGE2 在 KSHV 发病机制中的作用
- 批准号:
7554069 - 财政年份:2008
- 资助金额:
$ 21.88万 - 项目类别:
Role of Cyclooxygenase-2 and PGE2 in KSHV pathogenesis
Cyclooxygenase-2 和 PGE2 在 KSHV 发病机制中的作用
- 批准号:
7686184 - 财政年份:2008
- 资助金额:
$ 21.88万 - 项目类别:
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