Serpin Modulation of Inflammatory Vasculitis; Potential for Immunomodulatory Ther
炎症性血管炎的丝氨酸蛋白酶抑制剂调节;
基本信息
- 批准号:7830729
- 负责人:
- 金额:$ 50万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-30 至 2011-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdverse effectsAdverse eventAneurysmAngioplastyAnimal ModelAnti-Inflammatory AgentsAnti-inflammatoryAntibody FormationAntigensAortic Arch SyndromesAreaArterial Fatty StreakArteriesArteritisArthritisAtherosclerosisBlindnessBlood VesselsCD4 Positive T LymphocytesCanadaCellsCerebral IschemiaClinical TrialsCoagulation ProcessCollagenCollagen ArthritisConnective TissueCoronaryCytolysisDendritic CellsDevelopmentDiagnosisDilatation - actionDiseaseEarly DiagnosisElastinEmergency SituationEnzymesEquilibriumFactor XaFigs - dietaryGiant CellsGrowthHelper-Inducer T-LymphocyteHemorrhageImmuneImmune responseImplantInfarctionInfectionInflammationInflammatoryInflammatory ResponseInfusion proceduresInjuryInvadedInvestigationLaboratory ResearchLondonLymphocyte SubsetMatrix MetalloproteinasesMedialMediatingMedicalMethotrexateModelingMolecular TargetMorbidity - disease rateMyocardialMyocardial InfarctionMyocardial IschemiaMyxoma virusNeuronsOperative Surgical ProceduresOrganPan GenusPathway interactionsPatientsPeptide HydrolasesPhasePilot ProjectsPlasminPlasminogen Activator Inhibitor 1PrednisonePreventionRare DiseasesReportingResearchResearch DesignResearch PersonnelResearch ProposalsRiskRodent ModelRoleRuptureRuptured AneurysmSerine ProteaseSerine Proteinase InhibitorsSerpinsShockSiteStagingStentsSteroidsStrokeStroke VolumeSyndromeSystemT-LymphocyteTNF geneTakayasu&aposs ArteritisTemporal ArteritisTestingTherapeuticTherapeutic AgentsTherapeutic InterventionThrombosisTimeTissuesTranslational ResearchTransplantationUrokinaseVascular DiseasesVasculitisVirusWithholding TreatmentWorkacute coronary syndromeartery occlusionbasecerebrovasculardesigninflammatory markerinflammatory modulationinhibitor/antagonistinnovationmacrophagemonocytemortalitymouse modelnervous system disorderneuroserpinnovel strategiesnovel therapeutic interventionpreventpublic health relevancereceptorrepairedresearch studyresponseserpin-2successtherapy developmentvascular inflammationviron
项目摘要
DESCRIPTION (provided by applicant): Serpin Modulation of Inflammatory Vasculitis; Potential for Immunomodulatory Therapy The broad challenge areas applicable for this research proposal are 1) 15-OD(ORDR)-101* Pilot projects for prevention, early detection and treatment of rare diseases, 2) 15-NS-104 Early-stage therapy development, or 3) NSP - 15-NS-103 Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease. In broad strokes, the proposal presented here is a translational research study that addresses the more rare inflammatory vasculitic syndromes, Takayasu's disease (TKD) and Giant Cell Temporal Arteritis (GCTA). This work is designed to identify new molecular targets, to examine the feasibility of a new approach to treatment of inflammatory vasculitis, and to provide 'proof of principal' for therapeutic intervention with a new class of anti-inflammatory serine protease inhibitor (serpin) therapeutics. Takayasu's Disease (TKD) and Giant Cell Temporal Arteritis (GCTA) are pan-vasculitic syndromes, causing devastating disease with inflammatory cell mediated damage to all tissue layers of medium and large vessel arteries. Inflammatory vasculitis (IVS) ranges from rarer disorders such as TKD (2.6/million) and GCTA (20-200/100,000) to the arterial inflammation associated with atherosclerosis and aneurysm formation. Inflammatory cell invasion is characterized by invading adventitial and medial dendritic cells, macrophage, T lymphocytes, specifically T helper 1 (TH1) subpopulations, and giant cells, with attendant elastic layer degradation. This inflammation accelerates plaque formation and arterial occlusion or conversely arterial aneurysm formation, manifesting as sudden loss of vision, stroke, myocardial ischemia, aortic arch syndrome, and aneurysm rupture. Once diagnosed, the IVS are considered medical emergencies. Current treatment is limited to ASA and prednisone and long-term steroid treatment is associated with significant adverse events in up to 60% of patients. Other newer medical treatments such as TNF inhibitors and methotrexate have had only partial success in limited subsets of patients. Surgical interventions for occlusive or aneurysmal vascular changes is based upon watchful surveillance with potential high associated morbidity and mortality. Even with treatment, disease can progress and recur with cessation of treatment. New therapeutic approaches are thus needed and treatments targeting inflammatory cell activation and invasion have potential to prevent progression or to stabilize vascular areas at risk. Serine proteases in the thrombolytic cascade have been identified as activators of inflammatory cell responses in atherosclerosis and aneurysm models. Two innovative therapeutic approaches, based upon the infusion of serpins, one derived from a myxoma virus, Serp-1, and one mammalian serpin, neuroserpin (NSP), have been investigated in our research laboratory with proven anti-inflammatory actions in atherosclerosis (Fig/s 2 & 3), transplant vasculopathy, and collagen-induced arthritis in animal models. NSP is expressed by neurons, monocytes, and multiple organs, and is reported to reduce stroke volume in rodent models and in recent work from our lab, reduced transplant vasculopathy (Fig 1, Research Proposal). These serpins target protease cascades in the clot dissolving thrombolytic (uPA, tPA for Serp-1 and NSP; plasmin for Serp-1 ) and clot forming thrombotic pathways (fXa for Serp-1). These proteases have been associated with increased inflammatory cell invasion and matrix degradation both by our group and also other investigators. Treatment with either Serp-1 or NSP alters the balance of TH1 and TH2 activation with reduced TH1. Serp-1 represents a new class of virus-derived anti-inflammatory immunomodulatory therapeutic agents and we have recently successfully tested Serp-1 in a phase 2A clinical trial in acute coronary syndrome patients with a significant reduction in circulating markers for inflammation. No significant adverse events were detected (proprietary information, Viron Therapeutics, Inc. London, Canada). In summary, these studies are designed to assess the potential role of thrombolytic proteases, receptors, and regulatory serpins, specifically uPA, uPAR, and PAI-1, as molecular targets in Inflammatory Vasculitic (TKD and GCTA) disease and to assess the potential for serpin-derived therapies. This work will have potential for broad application to other forms of inflammatory vasculitis such as more common atherosclerotic plaque and aneurysm formation. With these studies we will conduct an intensive analysis into the role of thrombolytic serine proteases, serpins and receptors in mouse models of aggressive vasculitic disorders, specifically Giant Cell Temporal Arteritis (GCTA) and Takayasu's Disease (TKD), that cause sudden blindness, pulseless vessel occlusions, strokes, heart attacks, and aneurysms. The thrombolytic serine protease enzymes in the clot lysis pathway initiate collagen breakdown and aneurysm formation and serine proteinase inhibitors (serpins) protect against protease activation. We will test the therapeutic potential of two anti-inflammatory serpins for treatment of GCTA and TKD, and their capacity to actively modify T Helper (TH) cell responses. We have successfully tested one of these serpins, Serp-1, in a small phase 2A clinical trial for anti-inflammatory activity in unstable coronary syndromes (Viron Therapeutics, Inc; proprietary information).
PUBLIC HEALTH RELEVANCE: With these studies we will conduct an intensive analysis into the role of thrombolytic serine proteases, serpins and receptors in mouse models of aggressive vasculitic disorders, specifically Giant Cell Temporal Arteritis (GCTA) and Takayasu's Disease (TKD), that cause sudden blindness, pulseless vessel occlusions, strokes, heart attacks, and aneurysms. The thrombolytic serine protease enzymes in the clot lysis pathway initiate collagen breakdown and aneurysm formation and serine proteinase inhibitors (serpins) protect against protease activation. We will test the therapeutic potential of two anti-inflammatory serpins for treatment of GCTA and TKD, and their capacity to actively modify T Helper (TH) cell responses. We have successfully tested one of these serpins, Serp-1, in a small phase 2A clinical trial for anti-inflammatory activity in unstable coronary syndromes (Viron Therapeutics, Inc; proprietary information).
描述(由申请人提供):炎性血管炎的丝氨酸蛋白酶调节;适用于本研究计划的广泛挑战领域包括:1)15-OD(ORDR)-101*预防、早期检测和治疗罕见疾病的试点项目,2)15-NS-104早期治疗开发,或3)NSP - 15-NS-103神经系统疾病新治疗方法的“概念验证”示范。在广泛性中风中,本文提出的建议是一项针对更罕见的炎性血管综合征,Takayasu病(TKD)和巨细胞颞动脉炎(GCTA)的转化性研究。这项工作旨在确定新的分子靶点,研究治疗炎性血管炎的新方法的可行性,并为新型抗炎丝氨酸蛋白酶抑制剂(丝氨酸蛋白酶抑制剂)治疗干预提供“主要证据”。Takayasu病(TKD)和巨细胞颞动脉炎(GCTA)是泛血管综合征,引起炎症细胞介导的中、大血管动脉所有组织层损伤的毁灭性疾病。炎症性血管炎(IVS)的范围从罕见疾病如TKD(260 /百万)和GCTA(20-200/100,000)到动脉粥样硬化和动脉瘤形成相关的动脉炎症。炎症细胞侵袭的特征是侵袭外膜和内侧树突状细胞、巨噬细胞、T淋巴细胞,特别是辅助性T细胞1 (TH1)亚群和巨细胞,并伴有弹性层降解。这种炎症加速斑块的形成和动脉闭塞或相反动脉动脉瘤的形成,表现为突然失明、中风、心肌缺血、主动脉弓综合征和动脉瘤破裂。一旦确诊,IVS被认为是医疗紧急情况。目前的治疗仅限于ASA和泼尼松,长期类固醇治疗与高达60%的患者的严重不良事件相关。其他较新的药物治疗,如肿瘤坏死因子抑制剂和甲氨蝶呤,在有限的患者亚群中仅取得部分成功。闭塞性或动脉瘤性血管改变的手术干预是建立在密切监测的基础上的,潜在的高相关发病率和死亡率。即使接受了治疗,疾病也会随着停止治疗而进展和复发。因此,需要新的治疗方法,针对炎症细胞激活和侵袭的治疗有可能阻止进展或稳定危险的血管区域。在动脉粥样硬化和动脉瘤模型中,溶栓级联中的丝氨酸蛋白酶已被确定为炎症细胞反应的激活剂。两种基于蛇形蛋白输注的创新治疗方法,一种来自粘液瘤病毒Serp-1,另一种来自哺乳动物蛇形蛋白neuroserpin (NSP),已经在我们的研究实验室进行了研究,在动物模型中证实了对动脉粥样硬化(图2和3)、移植血管病变和胶原诱导关节炎的抗炎作用。NSP由神经元、单核细胞和多个器官表达,据报道,在啮齿动物模型中,NSP可以减少脑卒中体积,在我们实验室最近的工作中,NSP可以减少移植血管病变(图1,研究计划)。这些蛇蛋白靶向蛋白酶级联作用于溶栓血栓(uPA, tPA用于Serp-1和NSP;纤溶酶用于Serp-1)和血栓形成途径(fXa用于Serp-1)。这些蛋白酶与炎性细胞侵袭和基质降解的增加有关。用Serp-1或NSP治疗会改变TH1和TH2激活的平衡,使TH1减少。Serp-1代表了一类新的病毒衍生的抗炎免疫调节治疗剂,我们最近在急性冠状动脉综合征患者的2A期临床试验中成功地测试了Serp-1,其循环炎症标志物显着减少。未检测到显著不良事件(专有信息,Viron Therapeutics, Inc.)。伦敦,加拿大)。总之,这些研究旨在评估溶栓蛋白酶、受体和调节性蛇蛋白(特别是uPA、uPAR和PAI-1)作为炎症性血管管炎(TKD和GCTA)疾病分子靶点的潜在作用,并评估蛇蛋白衍生疗法的潜力。这项工作将有潜力广泛应用于其他形式的炎症性血管炎,如更常见的动脉粥样硬化斑块和动脉瘤形成。通过这些研究,我们将深入分析溶栓丝氨酸蛋白酶、蛇形蛋白和受体在侵袭性血管疾病小鼠模型中的作用,特别是巨细胞性颞动脉炎(GCTA)和高松病(TKD),这两种疾病会导致突然失明、无脉性血管闭塞、中风、心脏病发作和动脉瘤。凝块溶解途径中的溶栓丝氨酸蛋白酶启动胶原分解和动脉瘤形成,丝氨酸蛋白酶抑制剂(丝氨酸蛋白酶抑制剂)可防止蛋白酶激活。我们将测试两种抗炎蛇形蛋白治疗GCTA和TKD的治疗潜力,以及它们主动改变T辅助(TH)细胞反应的能力。我们已经在一项小型2A期临床试验中成功测试了其中一种蛇形蛋白,Serp-1,用于不稳定冠状动脉综合征的抗炎活性(Viron Therapeutics, Inc;专有信息)。
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(2)
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Alexandra Rose Lucas其他文献
Alexandra Rose Lucas的其他文献
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{{ truncateString('Alexandra Rose Lucas', 18)}}的其他基金
Serpin Modulation of Inflammatory Vasculitis; Potential for Immunomodulatory Ther
炎症性血管炎的丝氨酸蛋白酶抑制剂调节;
- 批准号:
7939744 - 财政年份:2009
- 资助金额:
$ 50万 - 项目类别:
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