Red light mediated trafficking of microvesicles as a mechanism for vasodilation

本申请是基于以下前提而构思的：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是无效的。PAD目前影响 超过800万美国人，随着我们国家的老龄化，将影响更多的人。治疗受试者的医疗保健费用 是显著的（医疗保险每年40亿美元），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种成本和疗效的趋势 曲线该提案试图通过认识到PAD导致的内皮功能障碍来改变这种模式 阻止正常的血流恢复，因为通过其同源酶一氧化氮的产生， 氧化物合酶受损。我们已经发现，内皮细胞囊泡内形成的一氧化氮（NO）前体， 通过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。最重要的是 这种自分泌因子的产生和释放在缺乏一氧化氮合酶的情况下扩张动脉/小动脉 （NOS）。红光的作用与临床相关，因为我们已经确定了血流的显著升高 当健康受试者和PAD患者的腓肠肌暴露于红光时。的 本申请的方法将是评估这些基于硫醇的NO囊泡在健康条件下的产生 和氧化应激，表征细胞内机制， 囊泡运输和NO前体囊泡的释放，并证实了我们在血管中获得的发现， 患有和不患有易受氧化应激影响的疾病的人类受试者。我们希望收集的数据将 确定含有NO前体分子的囊泡可以增加的机制， 内皮功能障碍和增强灌注。与兽医的相关性：PAD是一种昂贵且高度 严重影响退伍军人的疾病红光有可能非侵入性地 通过操纵囊泡中产生的细胞内NO前体来增加血流量。这一发现 一种新的干预措施，通过避免病态的手术，具有降低成本和改善症状的巨大潜力。 程序.红光疗法的更广泛的临床影响不能完全实现，直到机制， 红光释放这种血管扩张机制被识别。

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 because the production of nitric oxide through its cognate enzyme nitric oxide synthase is impaired. We have found nitric oxide (NO) precursors formed within endothelial vesicles to be stimulated by red light energy to release NO and produce a stable NO bound vasodilator. Most importantly the production and 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 production of these thiol based NO vesicles in healthy conditions and oxidative stress by using ex vivo and cell culture techniques, characterize the intracellular mechanism for vesicle transport and release of the NO precursor vesicle, and confirm our findings in vessels obtained from human subjects with and without diseases predisposed to oxidative stress. We expect the data collected will identify the mechanisms by which vesicles containing NO precursor molecules can be increased, improve endothelial dysfunction and enhance perfusion. RELEVANCE TO VETERANS: PAD is a costly and highly morbid disease which disproportionately affects our veterans. Red light has the potential to noninvasively increase blood flow through the manipulation of intracellular NO precursors produced in vesicles. This finding is a novel intervention which has great potential to reduce costs and improve symptoms by avoiding morbid surgical procedures. The broader clinical impact of red light therapy cannot be fully realized until the mechanism by which red light releases this vasodilator mechanism is identified.