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

本申请是基于在某些疾病中，例如外周动脉 疾病（PAD），传统疗法在治疗症状和相关疾病方面无效。 病态PAD目前影响着800多万美国人，随着我们的发展， 国家年龄。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阻止了适当的血流恢复（血管舒张和血管生成），因为 一氧化氮通过其同源酶一氧化氮合酶的产生受到损害。我们有 在血液和组织中发现了一氧化氮（NO）前体，这些前体被红光能量刺激 以释放NO并产生稳定的NO结合的血管扩张剂。此外，释放这 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。的 红光的作用是临床相关的，因为我们已经确定了血流量的显着升高， 当健康受试者和PAD患者的腓肠肌暴露于红色 光本申请中的方法将是评估这些铁和硫醇基化合物的影响。 NO前体使用生物化学和细胞培养技术，优化小鼠中的光传递 亚急性后肢缺血模型（模拟临床PAD），并证实了我们在人类中的发现 PAD患者。我们希望收集的数据将确定NO 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。

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.