Evaluating Novel Multi-kinase Peptide Inhibitors as a Treatment for Rheumatoid Ar
评估新型多激酶肽抑制剂治疗类风湿性关节炎的作用
基本信息
- 批准号:8591485
- 负责人:
- 金额:$ 21.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-30 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAffectAnchorage-Independent GrowthAnimal ModelAnimalsAnkleAntihypertensive AgentsAntioxidantsApoptosisApoptoticAtherosclerosisAutoimmune ProcessBCL2 geneBindingBiological AssayBiological MarkersBone MatrixBone ResorptionCCL2 geneCancer PatientCartilageCattleCell SurvivalChronicClinicalCollagenDataDepositionDiseaseDisease ProgressionEGFR Protein OverexpressionEnzyme-Linked Immunosorbent AssayEnzymesEpidermal Growth Factor ReceptorEvaluationExhibitsExtracellular MatrixFeedbackFibroblastsGoalsGrowth FactorHumanHyperplasiaI-kappa B ProteinsIL8 geneIn VitroInflammationInflammatoryInsulin ReceptorInterleukin-1Interleukin-6JointsKneeLesionLife ExpectancyLymphocyteMAPK14 geneMAPK8 geneMacrophage Inflammatory Protein-1Malignant NeoplasmsMediator of activation proteinMilkMilk ProteinsModelingModificationMolecularOxidative StressPathologic ProcessesPathway interactionsPatientsPeptidesPhosphotransferasesPlayPopulationProductionPropertyProtein Tyrosine KinaseProto-Oncogene Proteins c-aktQuality of lifeRANTESRattusReactive Oxygen SpeciesResearchResistanceRheumatoid ArthritisRoleSerumSignal PathwaySignal TransductionSignaling MoleculeSuperoxide DismutaseSynovial FluidSynovial MembraneTNF geneTdT-Mediated dUTP Nick End Labeling AssayTestingTherapeuticTumor Necrosis Factor-alphaVascular Endothelial Growth Factor ReceptorVascular Endothelial Growth Factor Receptor-2Vascular Endothelial Growth FactorsWestern BlottingZincalpha Lactalbuminangiogenesisantimicrobialarthropathiesbasebonecaspase-3cost effectivecytokinedisabilitydosagehuman TNF proteinin vivoinhibitor/antagonistneutrophilnoveloxidationphase 1 studyphase 2 studypublic health relevanceresearch studytumor
项目摘要
DESCRIPTION (provided by applicant): Cancer and rheumatoid arthritis (RA) share remarkably similar pathogenic pathways. For example, in both cancer and RA, angiogenesis, chronic inflammation and reactive oxygen species create a negative feedback loop that accelerates disease progression. In the synovium of RA patients, fibroblast-like synoviocytes (RA- FLS) has features of tumor-like transformation including anchorage-independent growth, adhesion to the extracellular matrix of cartilage, resistance to apoptotic signaling, and invasiveness to cartilage and bone. We have isolated a novel milk peptide mixture (AX-3) that inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 2 (VEGFR2), and insulin receptor (IR). In vivo, AX-3 exhibits anti-cancer activity, increases the level of antioxidant enzyme Superoxide Dismutase, and reduces pro-inflammatory factors TNF-alpha, MCP-1, and RANTES. Recently, we further identified the active component of AX-3. These recent data and the understanding that inflammation, angiogenesis, hyperplasia, and oxidative stress are crucial mediators of RA led us to investigate the potential of AX-3 and its active component as therapeutic candidates for treating rheumatoid arthritis. In Specific Aim 1, AX-3 and its active component will be tested for their ability to induce apoptosis in RA-FLS. At lower dosages, the peptides will be assessed for inhibition of pro-inflammatory factor expressions in RA-FLS, and inhibition of several signaling pathways will also be tested. In Specific Aim 2, the in vivo effects of AX-3 and its active component on joint degradation and various biomarkers will be assessed using a collagen- induced RA rat model. In phase II study we will continue further molecular characterization and pharmacological studies based on the preliminary in vitro and animal results. The long term goal of this project is to develop a safe, effective, and cost-efficient therapy to treat RA.
描述(由申请人提供):癌症和类风湿性关节炎(RA)具有非常相似的致病途径。例如,在癌症和 RA 中,血管生成、慢性炎症和活性氧会产生负反馈循环,加速疾病进展。在RA患者的滑膜中,成纤维细胞样滑膜细胞(RA-FLS)具有肿瘤样转化的特征,包括锚定非依赖性生长、与软骨细胞外基质的粘附、对凋亡信号的抵抗以及对软骨和骨的侵袭性。我们分离出一种新型牛奶肽混合物 (AX-3),它可以抑制表皮生长因子受体 (EGFR)、血管内皮生长因子受体 2 (VEGFR2) 和胰岛素受体 (IR) 的酪氨酸激酶活性。在体内,AX-3 表现出抗癌活性,增加抗氧化酶超氧化物歧化酶的水平,并减少促炎因子 TNF-α、MCP-1 和 RANTES。最近,我们进一步鉴定了AX-3的活性成分。这些最新数据以及对炎症、血管生成、增生和氧化应激是 RA 关键介质的认识促使我们研究 AX-3 及其活性成分作为治疗类风湿性关节炎的候选药物的潜力。在具体目标 1 中,将测试 AX-3 及其活性成分在 RA-FLS 中诱导细胞凋亡的能力。在较低剂量下,将评估这些肽对 RA-FLS 中促炎因子表达的抑制作用,并且还将测试对多种信号传导途径的抑制作用。在具体目标 2 中,将使用胶原诱导的 RA 大鼠模型评估 AX-3 及其活性成分对关节退化和各种生物标志物的体内影响。在II期研究中,我们将根据初步的体外和动物结果继续进一步的分子表征和药理学研究。该项目的长期目标是开发一种安全、有效且经济高效的 RA 治疗方法。
项目成果
期刊论文数量(0)
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David Men-Hwei Tsai其他文献
David Men-Hwei Tsai的其他文献
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APOPTOSIS INDUCING PROTEINS AS ANTICANCER AGENT
细胞凋亡诱导蛋白作为抗癌剂
- 批准号:
2542515 - 财政年份:1997
- 资助金额:
$ 21.71万 - 项目类别:
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环状 AMP 结合蛋白和 RAS 功能
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3503439 - 财政年份:1992
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$ 21.71万 - 项目类别:
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