The Novel Approach of RNA Based Therapeutic Technologies
基于 RNA 的治疗技术的新方法
基本信息
- 批准号:7560006
- 负责人:
- 金额:$ 37.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-02-01 至 2012-01-31
- 项目状态:已结题
- 来源:
- 关键词:AnimalsAnti-Inflammatory AgentsAnti-inflammatoryAntiatherogenicAortaApolipoproteins BApplications GrantsArterial Fatty StreakArteriesAtherosclerosisBiological AssayBlood VesselsC57BL/6 MouseCardiacCardiovascular systemCatalytic DomainCatalytic RNACellsCessation of lifeCholesterolCleaved cellClinicalCollaborationsComplementConsensus SequenceCoronaryCoronary ArteriosclerosisDevelopmentDietDiseaseElementsEnzymesEsterified Fatty AcidsEtiologyEventFamilial HypercholesterolemiaGene ExpressionGenesGeneticGoalsHeart DiseasesHepatocyteHumanHydrolysisHyperlipidemiaHypobetalipoproteinemiaIn VitroInflammationInflammatoryInflammatory ResponseIschemic StrokeKupffer CellsLDL Cholesterol LipoproteinsLaboratoriesLeadLengthLifeLipidsLipoproteinsLong-Term EffectsLow Density Lipoprotein oxidationLow-Density LipoproteinsLysophosphatidylcholinesMeasuresMediatingMessenger RNAMetabolismModelingModificationMolecularMolecular ConformationMolecular WeightMorbidity - disease rateMusNucleotidesOperative Surgical ProceduresOutcome StudyOxidative StressPathway interactionsPatientsPharmacotherapyPhospholipase A2PhospholipidsPlasmaPreventionProductionPropertyProteinsRB1 geneRNARiskSiteSocietiesStagingStructureTechnologyTestingTherapeuticTherapeutic Agentsadeno-associated viral vectoratherogenesisbasecardiovascular risk factorcerebral arterydaltondesigngene therapyhammerhead ribozymein vitro Assayin vivoinflammatory markerinnovationinsightlipid mediatorlipoprotein-associated phospholipase A(2)low density lipoprotein inhibitorlow density lipoprotein triglyceridemRNA Expressionmacrophagemortalitymouse modelnovelnovel strategiesnovel therapeuticsparticlepremature atherosclerosispreventstemvector
项目摘要
DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to design and develop novel strategies for regulating the development and progression of atherosclerosis and to provide new insights into the application of target specific hammerhead ribozymes for inhibiting gene expression. Our ultimate goal will be to develop human gene therapy strategies for alleviating atherosclerosis, which is responsible for most clinical manifestations of coronary artery disease and ischemic stroke. Atherosclerosis is recognized as an inflammatory disease, with the presence of LDL in the intima (subendothelial matrix) leading to inflammatory responses, oxidative stress, and plaque formation. Our laboratory has developed a genetically defined mouse model of atherosclerosis (LDb mice), which has a plasma lipoprotein profile that resembles humans with hyperlipidemia and results in diet-independent atherosclerosis. The etiology of atherosclerosis in this model mimics that of humans. In this application, we plan to develop novel strategies using minimal and tertiary stabilized hammerhead ribozymes to target two genes (apolipoprotein B mRNA and lipoprotein-associated phospholipase A2) simultaneously and will test the effect of this strategy on atherosclerosis development in LDb mice. We hypothesize that inhibiting gene expression of apoB and Lp-PLA2 mRNA will decrease oxidation of LDL, reduce the inflammatory response, and inhibit atherosclerosis development in LDb mice. We will use the double-stranded chimeric adeno-associated viral vector AAV2/8 to deliver these hammerhead ribozyme molecules to mice and will examine the persistence of both vectors and ribozyme gene expression in vivo. This study will allow us to understand the molecular mechanisms used by ribozymes to regulate gene expression and the ability of these ribozymes to inhibit atherosclerosis development. In summary, this study will provide a novel therapeutic treatment for coronary atherosclerosis and provide evidence of the efficiency and efficacy of RNA based molecules as potential therapeutic agents.
描述(由申请人提供):本提案的长期目标是设计和开发调节动脉粥样硬化发生和进展的新策略,并为应用靶标特异性锤头核酶抑制基因表达提供新见解。我们的最终目标是开发缓解动脉粥样硬化的人类基因治疗策略,动脉粥样硬化是冠状动脉疾病和缺血性中风的大多数临床表现的原因。动脉粥样硬化被认为是一种炎症性疾病,内膜(内皮下基质)中低密度脂蛋白的存在会导致炎症反应、氧化应激和斑块形成。我们的实验室开发了一种基因定义的动脉粥样硬化小鼠模型(LDb 小鼠),其血浆脂蛋白谱与患有高脂血症的人类相似,可导致与饮食无关的动脉粥样硬化。该模型中动脉粥样硬化的病因学模仿了人类的病因学。在本申请中,我们计划开发新策略,使用最小和三级稳定锤头核酶同时靶向两个基因(载脂蛋白 B mRNA 和脂蛋白相关磷脂酶 A2),并将测试该策略对 LDb 小鼠动脉粥样硬化发展的影响。我们假设抑制 apoB 和 Lp-PLA2 mRNA 的基因表达将减少 LDL 的氧化,减少炎症反应,并抑制 LDb 小鼠动脉粥样硬化的发展。我们将使用双链嵌合腺相关病毒载体 AAV2/8 将这些锤头核酶分子传递给小鼠,并检查载体和核酶基因表达在体内的持久性。这项研究将使我们了解核酶调节基因表达的分子机制以及这些核酶抑制动脉粥样硬化发展的能力。 总之,这项研究将为冠状动脉粥样硬化提供一种新的治疗方法,并为基于 RNA 的分子作为潜在治疗剂的效率和功效提供证据。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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BA-BIE TENG其他文献
BA-BIE TENG的其他文献
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Active Immunity Targeted at PCSK9 for the Treatment of Hypercholesterolemia
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The Novel Approach of RNA Based Therapeutic Technologies
基于 RNA 的治疗技术的新方法
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The Novel Approach of RNA Based Therapeutic Technologies
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