Red light mediated trafficking of microvesicles as a mechanism for vasodilation

红光介导的微泡运输作为血管舒张的机制

• 批准号: 9890154
• 负责人: Nicole Lohr
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890154
• 关键词: Adhesions; Affect; Age; American; Amputation; Arteries; Atherosclerosis; Blood; Blood Vessels; Blood flow; Calcium; Cell Culture Techniques; Cell membrane; Cellular Stress; Chronic; Clinical; Data; Descriptor; Diabetes Mellitus; Disease; Drug Delivery Systems; Drug usage; Endothelial Cells; Endothelium; Enzymes; Exhibits; Exposure to; Failure; Gastrocnemius Muscle; Generations; Health Care Costs; Human; Hyperglycemia; Impairment; In Vitro; Incidence; Intervention; Ischemia; Kidney Diseases; Knowledge; Laboratories; Leukocytes; Light; Limb structure; Measures; Mediating; Medical; Medicare; Modality; Modeling; Morbidity - disease rate; Mus; Muscle; Nitric Oxide; Nitric Oxide Synthase; Nitrite Reductase; Operative Surgical Procedures; Oxidative Stress; Pain; Pathologic; Pathway interactions; Patients; Perfusion; Peripheral; Peripheral arterial disease; Pharmacotherapy; Phenotype; Phototherapy; Platelet aggregation; Population; Procedures; Production; Proteins; Reactive Oxygen Species; Recovery; S-Nitrosothiols; Severities; Smoking; Source; Sulfhydryl Compounds; Testing; Therapeutic; Tissues; Translating; Vascular Diseases; Vasodilation; Vasodilator Agents; Vesicle; Vesicle Transport Pathway; Veterans; arteriole; autocrine; base; chronic pain; clinically relevant; common treatment; comorbidity; comparison intervention; cost; db/db mouse; design; drug discovery; effective therapy; endothelial dysfunction; exosome; experimental study; high risk; human disease; human model; human subject; improved; improved outcome; ineffective therapies; limb ischemia; microvesicles; novel; novel drug class; prevent; response; symptom treatment; symptomatic improvement; traditional therapy; trafficking; trend; vesicle transport; vesicular release

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.

该应用程序的设想前提是，在某些疾病中，例如外周动脉疾病（PAD），