THE ROLE OF A-BETA SPECIES IN VASCULAR SMOOTH MUSCLE CELL AND CEREBRAL ARTERIOLE
A-β 物种在血管平滑肌细胞和脑小动脉中的作用
基本信息
- 批准号:8606781
- 负责人:
- 金额:$ 32.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-03-01 至 2016-01-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAlzheimer&aposs DiseaseAntibodiesApolipoprotein EApplications GrantsAssesBindingBlood VesselsBrainBrain InfarctionCause of DeathCell Culture TechniquesCell Surface ReceptorsCell physiologyCerebral Amyloid AngiopathyCerebral IschemiaCerebrovascular CirculationCerebrumDataDementiaDepositionEndothelial CellsFunctional disorderFutureGeneticGenetically Engineered MouseGoalsGrantImmunotherapyImpaired cognitionImpairmentIn VitroInfarctionLDL-Receptor Related Protein 1LinkMediatingMemoryMethodsMitochondriaMolecularMusNADPH OxidaseOutcomeOxidative StressPathologyPathway interactionsPatientsPhenotypePlayPredisposing FactorPredispositionPropertyReactive Oxygen SpeciesResearch PersonnelRiskRisk FactorsRoleSmooth Muscle MyocytesStagingStrokeTestingTg2576TherapeuticTransgenic MiceUnited StatesVascular Endothelial Cellagedamyloid peptidearteriolebasecerebrovasculareffective therapyheparanaseheparin proteoglycanimprovedin vivomonomerpeptide Apre-clinicalpreventpublic health relevanceresearch studytherapeutic developmenttherapy development
项目摘要
DESCRIPTION (provided by applicant): The role of A¿ species in vascular smooth muscle cell and cerebral arteriole dysfunction. Alzheimer's Disease (AD) is the leading cause of dementia; yet no therapy exists to slow or stop its progression. Recently, cerebrovascular (CV) pathology has been identified as a strong contributor to AD. Two key observations suggest that amyloid-¿ peptide (A¿) may play a role by either causing or increasing the susceptibility to cerebral ischemia. First, cerebral blood flow (CBF) is reduced in early stages of AD, and the reactivity of cerebral blood vessels is impaired - both of which have been linked to the vasoactive properties of A¿. Second, most AD patients develop A¿ deposits not only in brain but also in vessels - a condition known as cerebral amyloid angiopathy (CAA). CAA is a powerful risk factor for brain infarction and dementia, and is associated with severe CV dysfunction. A2 exists in several forms including soluble monomers (such as A¿40 and A¿42), soluble oligomers (toxic intermediate species), and insoluble fibrils (principle component of CAA). The former (primarily A¿40) and the latter (fibrillar A2 in the form of CAA) have been shown to powerfully alter CV function, while the vascular effects of A2 oligomers are not known. Our preliminary data suggest that the manner and extent to which monomeric A2 vs. fibrillar A2 cause CV dysfunction is different. We find that A¿ monomers cause a hyper-contractile vascular phenotype that is due to endothelial cell (EC) and vascular smooth muscle cell (VSMC) dysfunction that is mediated via reactive oxygen species (ROS), while A¿ fibrils in the form of CAA cause a hypo-contractile vascular phenotype that is primarily due to VSMC dysfunction that is mediated via ROS. We also identified a previously unrecognized contribution of ROS to CAA formation. The long-term objective of the proposed project is to test the central hypothesis that A¿ species powerfully and adversely affect the cerebral circulation by inducing VSMC-mediated arteriole dysfunction via an ROS- mediated pathway. The specific aims are 1) to determine whether A¿ species cause differential CV effects (hyper- vs. hypo-contractile impairment); 2) to determine the ROS pathways by which A¿ species cause VSMC and cerebral arteriole dysfunction; and 3) to determine the manner and extent to which ROS contribute to CAA formation, and to assess the functional benefits of reducing CAA via anti-ROS strategies. Methods used will include a) in vitro assessment of VSMC function after application of exogenous A¿ species; b) in vivo assessment of cerebral arteriole function in transgenic mice producing endogenous A¿ species; c) immunotherapy with anti-A¿ antibodies that bind A¿40, A¿42, A¿ oligomers, and/or A¿ fibrils; d) pharmacologic and genetic inhibition of NADPH oxidase; d) pharmacologic and genetic inhibition of the A2-binding cell surface receptors, LRP1 and HSPGs; and e) quantitation of CAA, A¿40, A¿42, APP, and ApoE. If successful, these studies will result in an improved understanding of the mechanisms underlying A¿-induced CV deficits and CAA formation. This will likely facilitate development of therapies targeting A¿ and its downstream effectors, which may ultimately improve the outcome of patients with AD, CAA, or both.
描述(由申请人提供):A¿ 的作用血管平滑肌细胞和脑小动脉功能障碍是导致痴呆的主要原因;但最近,脑血管 (CV) 病理学已被确定为导致痴呆的重要原因。两个关键观察结果表明淀粉样蛋白-¿肽 (A¿) 可能通过引起或增加脑缺血的易感性发挥作用。首先,AD 早期阶段脑血流量 (CBF) 减少,脑血管反应性受损 - 两者都会发生。与 A¿ 的血管活性特性有关其次,大多数 AD 患者会出现 A¿沉积物不仅存在于大脑中,而且存在于血管中 - 一种称为脑淀粉样血管病 (CAA) 的疾病是脑梗死和痴呆的重要危险因素,并且与严重的 CV 功能障碍相关,其中包括可溶性单体。例如 A¿40 和 A¿42)、可溶性低聚物(有毒中间体)和不溶性原纤维(CAA 的主要成分)。后者(CAA 形式的纤维状 A2)已被证明可以强有力地改变 CV 功能,而 A2 寡聚物的血管效应尚不清楚,我们的初步数据表明单体 A2 与纤维状 A2 导致 CV 的方式和程度。我们发现 A¿单体会导致血管过度收缩表型,这是由于内皮细胞(EC)和血管平滑肌细胞(VSMC)功能障碍是由活性氧(ROS)介导的,而A¿ CAA 形式的原纤维会导致血管收缩不良表型,这主要是由于 ROS 介导的 VSMC 功能障碍。我们还发现了 ROS 对 CAA 形成的一个先前未被认识的贡献。检验中心假设 A¿物种通过 ROS 介导的途径诱导 VSMC 介导的小动脉功能障碍,对脑循环产生强有力的不利影响。具体目标是 1) 确定 A¿物种引起不同的 CV 效应(收缩过度与收缩受损);2) 确定 A¿物种导致 VSMC 和脑小动脉功能障碍;3) 确定 ROS 促进 CAA 形成的方式和程度,并评估通过抗 ROS 策略减少 CAA 的功能益处。应用外源性 A 后 VSMC 功能b) 体内评估产生内源性A¿的转基因小鼠的脑小动脉功能种;c) 抗 A¿ 免疫疗法结合A的抗体40、A?? 42、A??低聚物,和/或A¿原纤维;d) NADPH 氧化酶的药理学和遗传抑制;d) A2 结合细胞表面受体、LRP1 和 HSPG 的药理学和遗传抑制;e) CAA、A¿ 40、A?? 42、APP 和 ApoE 如果成功,这些研究将加深对 A¿ 的机制的理解。 -诱导的 CV 缺陷和 CAA 形成,这可能会促进针对 A¿ 的疗法的开发。及其下游效应器,最终可能会改善 AD、CAA 或两者兼而有之的患者的预后。
项目成果
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