Red light mediated trafficking of microvesicles as a mechanism for vasodilation

该应用是在这样的前提下构思的：在某些疾病，例如外周动脉疾病(PAD)中， 传统疗法在治疗症状和相关疾病方面无效。PAD目前正在影响 超过800万美国人，并将随着我们国家的老龄化影响更多的人。治疗受试者的医疗费用 非常重要(根据联邦医疗保险，每年40亿美元)，大多数患者需要大量血管内和 外科手术包括截肢。药物治疗未能影响这一成本和疗效的趋势 曲线。这项建议试图通过认识到PAD所致的内皮功能障碍来改变这种范式 阻止正常的血流恢复，因为一氧化氮通过其同源酶NO产生 氧化合酶受损。我们发现在内皮小泡中形成的一氧化氮(NO)前体是 在红光能量的刺激下释放NO，产生稳定的NO结合的血管扩张剂。最重要的是 在没有一氧化氮合酶的情况下，这种自分泌因子的产生和释放可以扩张动脉/小动脉 (否)。红光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。 当健康人和PAD患者的腓肠肌暴露在红光下时。这个 这种应用的方法将是评估这些基于硫醇的无囊泡在健康条件下的产生 和氧化应激，通过体外和细胞培养技术，表征了细胞内的机制 囊泡运输和释放NO前体囊泡，并证实了我们在血管中的发现 患有和不患有疾病的受试者都容易受到氧化应激的影响。我们预计收集的数据将 确定不含前体分子的囊泡可以被增加、改善的机制 内皮功能障碍和增强血流灌注。与退伍军人相关：PAD是一种昂贵且高度 不成比例地影响我们退伍军人的病态疾病。红灯有可能非侵入性地 通过操纵细胞内产生的NO前体来增加血流量。这一发现是 一种通过避免病态手术来降低成本和改善症状的新型干预措施 程序。红光疗法的更广泛的临床影响只有通过以下机制才能完全实现 红光释放这种血管扩张剂的机制被识别出来。

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.