Small molecule NO precursors as a bioactive source of NO in vasodilation and angiogenesis
小分子 NO 前体作为血管舒张和血管生成中 NO 的生物活性来源
基本信息
- 批准号:9926301
- 负责人:
- 金额:$ 44.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAgeAmericanAmputationAnimal ModelAnkleArteriesBiochemicalBloodBlood VesselsBlood flowCardiovascular systemCell Culture TechniquesCellsCharacteristicsChemicalsChronicClinicalClinical TrialsDataDiabetes MellitusDiseaseElectromagneticsEndothelial CellsEndotheliumEnzymesExerciseExposure toGastrocnemius MuscleGrowthHealth Care CostsHealth systemHindlimbHome environmentHospitalizationHumanHyperlipidemiaHypotensionImpairmentIronIschemiaIsolated limb perfusionKnowledgeLasersLegLightMeasuresMediator of activation proteinMedicalMedicareMetabolicMorbidity - disease rateMuscleNOS3 geneNatureNitric OxideNitric Oxide DonorsNitric Oxide SynthaseObstructionOperative Surgical ProceduresPainPatientsPenetrationPerfusionPeripheralPeripheral arterial diseasePharmaceutical PreparationsPhototherapyPhysiologicalProductionQuality of lifeRecoveryRelaxationS-NitrosothiolsSignal TransductionSiteSkeletal MuscleSkinSkin TemperatureSmokingSourceSulfhydryl CompoundsSurfaceTestingTimeTissuesTranslatingVasodilationVasodilator Agentsameroidangiogenesisarterioleautocrinebasechronic pain patientchronic woundclinically relevantcostdesigndinitrosyl iron complexeffective therapyendothelial dysfunctionexperiencehuman subjectimprovedin vivoindexingineffective therapiesinflammatory milieuirradiationlimb ischemiamortalitymouse modelmyocardial infarct sizingnovel strategiespre-clinicalpreventside effectsmall moleculesuccesssymptom treatmenttraditional therapytreatment centertrend
项目摘要
This application is conceived on the premise that in certain diseases, e.g. peripheral artery
disease (PAD), traditional therapies are ineffective in the treatment of symptoms and related
morbidities. PAD currently impacts over 8 million Americans and will affect many more as our
nation ages. The health care costs to treat subjects are significant ($4 billion annually by
Medicare), with most patients requiring numerous endovascular and surgical procedures
including amputation. Medical therapy has failed to impact the trend in this cost and efficacy curve.
This proposal seeks to change this paradigm by recognizing the endothelial dysfunction attributed
to PAD prevents proper blood flow recovery (vasodilation and angiogenesis) because the
production of nitric oxide through its cognate enzyme nitric oxide synthase is impaired. We have
found nitric oxide (NO) precursors in blood and tissues which are stimulated by red light energy
to release NO and produce a stable NO bound vasodilator. Furthermore, the release of this
autocrine factor dilates arteries/arterioles in the absence of nitric oxide synthase (NOS). The
actions of red light are clinically relevant, as we have identified significant elevations in blood flow
when the gastrocnemius muscle of healthy subjects and patients with PAD are exposed to red
light. The approach in this application will be to assess the impact of these iron and thiol based
NO precursors using biochemical and cell culture techniques, optimize light delivery in a murine
model of subacute hindlimb ischemia (to mimic clinical PAD), and confirm our findings in human
subjects with PAD. We expect the data collected will identify the mechanisms by which NO
intracellular NO precursor molecules can be increased, improve endothelial dysfunction and
enhance limb perfusion.
构思该应用的前提是在某些疾病中,例如周围动脉
疾病(PAD),传统疗法对治疗症状和相关疾病无效
发病率。 PAD 目前影响着超过 800 万美国人,并将影响更多的人
民族时代。治疗受试者的医疗保健费用是巨大的(每年 40 亿美元)
医疗保险),大多数患者需要大量的血管内和外科手术
包括截肢。药物治疗未能影响该成本和疗效曲线的趋势。
该提案旨在通过认识到内皮功能障碍来改变这种范式
PAD 会阻碍正常的血流恢复(血管舒张和血管生成),因为
通过其同源酶一氧化氮合酶产生一氧化氮的能力受到损害。我们有
在红光能量刺激的血液和组织中发现一氧化氮 (NO) 前体
释放NO并产生稳定的NO结合血管舒张剂。此外,本次发布
在缺乏一氧化氮合酶 (NOS) 的情况下,自分泌因子会扩张动脉/小动脉。这
红光的作用具有临床意义,因为我们已经发现血流量显着升高
当健康受试者和 PAD 患者的腓肠肌暴露于红色时
光。本申请中的方法将评估这些基于铁和硫醇的影响
使用生化和细胞培养技术的 NO 前体优化小鼠体内的光传递
亚急性后肢缺血模型(模拟临床 PAD),并证实我们在人类中的发现
带有 PAD 的受试者。我们期望收集到的数据将确定 NO 的机制
可以增加细胞内NO前体分子,改善内皮功能障碍
增强肢体灌注。
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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Nicole Lohr其他文献
Nicole Lohr的其他文献
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{{ truncateString('Nicole Lohr', 18)}}的其他基金
Red light mediated trafficking of microvesicles as a mechanism for vasodilation
红光介导的微泡运输作为血管舒张的机制
- 批准号:
10477186 - 财政年份:2020
- 资助金额:
$ 44.98万 - 项目类别:
Red light mediated trafficking of microvesicles as a mechanism for vasodilation
红光介导的微泡运输作为血管舒张的机制
- 批准号:
10664941 - 财政年份:2020
- 资助金额:
$ 44.98万 - 项目类别:
Red light mediated trafficking of microvesicles as a mechanism for vasodilation
红光介导的微泡运输作为血管舒张的机制
- 批准号:
9890154 - 财政年份:2020
- 资助金额:
$ 44.98万 - 项目类别:
Small molecule NO precursors as a bioactive source of NO in vasodilation and angiogenesis
小分子 NO 前体作为血管舒张和血管生成中 NO 的生物活性来源
- 批准号:
10907267 - 财政年份:2019
- 资助金额:
$ 44.98万 - 项目类别:
Small molecule NO precursors as a bioactive source of NO in vasodilation and angiogenesis
小分子 NO 前体作为血管舒张和血管生成中 NO 的生物活性来源
- 批准号:
10406907 - 财政年份:2019
- 资助金额:
$ 44.98万 - 项目类别:
Small molecule NO precursors as a bioactive source of NO in vasodilation and angiogenesis
小分子 NO 前体作为血管舒张和血管生成中 NO 的生物活性来源
- 批准号:
10166902 - 财政年份:2019
- 资助金额:
$ 44.98万 - 项目类别:
Energy dependent reversal of endothelial dysfunction in wound healing
伤口愈合中内皮功能障碍的能量依赖性逆转
- 批准号:
9088108 - 财政年份:2015
- 资助金额:
$ 44.98万 - 项目类别:
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