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: 9926301
• 负责人: Nicole Lohr
• 金额: $ 44.98万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9926301
• 关键词: Acute; Affect; Age; American; Amputation; Animal Model; Ankle; Arteries; Biochemical; Blood; Blood Vessels; Blood flow; Cardiovascular system; Cell Culture Techniques; Cells; Characteristics; Chemicals; Chronic; Clinical; Clinical Trials; Data; Diabetes Mellitus; Disease; Electromagnetics; Endothelial Cells; Endothelium; Enzymes; Exercise; Exposure to; Gastrocnemius Muscle; Growth; Health Care Costs; Health system; Hindlimb; Home environment; Hospitalization; Human; Hyperlipidemia; Hypotension; Impairment; Iron; Ischemia; Isolated limb perfusion; Knowledge; Lasers; Leg; Light; Measures; Mediator of activation protein; Medical; Medicare; Metabolic; Morbidity - disease rate; Muscle; NOS3 gene; Nature; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Obstruction; Operative Surgical Procedures; Pain; Patients; Penetration; Perfusion; Peripheral; Peripheral arterial disease; Pharmaceutical Preparations; Phototherapy; Physiological; Production; Quality of life; Recovery; Relaxation; S-Nitrosothiols; Signal Transduction; Site; Skeletal Muscle; Skin; Skin Temperature; Smoking; Source; Sulfhydryl Compounds; Surface; Testing; Time; Tissues; Translating; Vasodilation; Vasodilator Agents; ameroid; angiogenesis; arteriole; autocrine; base; chronic pain patient; chronic wound; clinically relevant; cost; design; dinitrosyl iron complex; effective therapy; endothelial dysfunction; experience; human subject; improved; in vivo; indexing; ineffective therapies; inflammatory milieu; irradiation; limb ischemia; mortality; mouse model; myocardial infarct sizing; novel strategies; pre-clinical; prevent; side effect; small molecule; success; symptom treatment; traditional therapy; treatment center; trend

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。