Small molecule NO precursors as a bioactive source of NO in vasodilation and angiogenesis

这种应用是在这样的前提下构思的：在某些疾病中，例如周围动脉 疾病(PAD)，传统疗法在治疗症状及相关方面均无效 病态。PAD目前影响着800多万美国人，并将影响更多的人，因为我们的 民族时代。治疗受试者的医疗保健成本很高(到 联邦医疗保险)，大多数患者需要许多血管内和外科手术 包括截肢。药物治疗未能影响这一成本和疗效曲线的趋势。 这项建议试图通过认识到内皮功能障碍归因于 PAD会阻止正常的血流恢复(血管扩张和血管生成)，因为 通过其同源酶一氧化氮合酶产生一氧化氮受到损害。我们有 在血液和组织中发现受红光能量刺激的一氧化氮(NO)前体 释放NO并产生稳定的NO结合的血管扩张剂。此外，这一消息的发布 自分泌因子在没有一氧化氮合酶(NOS)的情况下扩张动脉/小动脉。这个 红灯的作用在临床上是相关的，因为我们已经发现血液流量显著升高。 健康受试者和PAD患者的腓肠肌暴露于红色时 灯。该应用中的方法将评估这些铁和硫醇基团的影响 没有使用生化和细胞培养技术的前体，优化了小鼠的光传递 亚急性后肢缺血模型(模拟临床PAD)，并在人类身上证实了我们的发现 有PAD的受试者。我们希望收集到的数据将确定通过哪些机制 细胞内NO前体分子增加，改善内皮功能障碍， 增强四肢的血流灌注。

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.