Energy dependent reversal of endothelial dysfunction in wound healing

伤口愈合中内皮功能障碍的能量依赖性逆转

• 批准号: 9088108
• 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: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9088108
• 关键词: Acidosis; Affect; Age; Amputation; Animal Model; Animals; Attenuated; Binding; Blood Circulation; Blood Vessels; Blood flow; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cells; Chemicals; Chronic; Clinical; Coronary; Coronary Arteriosclerosis; Cytosol; Data; Development; Diabetes Mellitus; Dilatation - action; Disease; E-Selectin; Electromagnetic Energy; Endothelial Cells; Endothelium; Evaluation; Exhibits; Future; Healed; Heart; Heme; Heme Group; Homeostasis; Human; Hyperlipidemia; Hypertension; Hypoxia; Impaired wound healing; Inflammation Mediators; Inflammatory; Interleukin-1; Interleukin-6; Investigation; Iron; K-Series Research Career Programs; Knockout Mice; Lead; Left; Light; Maintenance; Measures; Metabolism; Mitochondria; Modality; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle relaxation phase; NOS3 gene; Nitric Oxide; Nitrite Reductase; Nitrites; Oxidants; Patients; Perfusion; Peripheral arterial disease; Phototherapy; Physiological; Plague; Population; Post-Traumatic Stress Disorders; Preparation; Process; Production; Proteins; Risk Factors; Set protein; Signal Transduction; Signaling Molecule; Site; Skeletal Muscle; Skin; Smooth Muscle; Sodium Nitrite; Source; Stress; Sulfhydryl Compounds; Supplementation; System; Testing; Thrombosis; Thrombus; Tissues; Tobacco use; Transgenic Organisms; United States Department of Veterans Affairs; Vasodilation; Vasospasm; Veterans; Visit; Wound Healing; XDH gene; angiogenesis; base; cardiovascular risk factor; chronic pain; chronic wound; cost; cytochrome c oxidase; db/db mouse; deoxyhemoglobin; deoxymyoglobin; effective therapy; effectiveness measure; endothelial dysfunction; healing; health care delivery; high risk; hypercholesterolemia; improved; inflammatory marker; interest; novel; novel therapeutics; oxidant stress; paracrine; public health relevance; regenerative; repaired; response; synergism; targeted treatment

 DESCRIPTION (provided by applicant): The endothelial lining produces key substances such as nitric oxide (NO) for the maintenance of vascular homeostasis. Cardiovascular diseases affecting the heart (coronary artery disease) and skeletal muscle (peripheral artery disease) can be attributed to a pathological transformation of the endothelium from a NO producing cell which is vasoactive, antithrombotic, and regenerative; to a cell which exhibits impaired vasodilation, increased thrombus formation, and a lost capacity for cellular repair because NO production is inhibited. Cardiovascular risk factors such as age, hypertension, hyperlipidemia, PTSD and tobacco use induce inflammatory signals which stimulate this pathological transformation. One manifestation of endothelial dysfunction is the chronic ulcerative wounds seen in patients with diabetes and peripheral artery disease. Our nation's veterans are at high risk for chronic ulcerated wounds because they possess many of these cardiac risk factors. This Veterans Administration Career Development Award (CDA-2) is conceived on the premise that light energy produces a novel means for increasing NO which is scavenged by endothelial dysfunction, and in the future may lead to the development of novel vascular therapies targeted to improve wound healing. These investigations are directed to test the hypothesis that light energy can release NO specifically to ischemic tissues. This alternative source of NO has the potential to improve endothelial function in regions where NO production is attenuated, thereby improving vessel reactivity and wound healing. Our hypothesis will be tested by targeting a defined set of proteins known to produce and bind NO and measure its production before and after energy exposure. We will also measure the impact of energy to stimulate vasodilation and wound healing under physiological conditions and inflammatory stress. The information gained from this investigation will expand our understanding of where important NO stores in the cell exist, and how energy can stimulate these stores to improve endothelial cell homeostasis in inflammatory disease.

 描述（由申请人提供）： 内皮层产生维持血管稳态的关键物质，例如一氧化氮（NO）。影响心脏（冠状动脉疾病）和骨骼肌（外周动脉疾病）的心血管疾病可归因于内皮细胞从具有血管活性、抗血栓和再生作用的一氧化氮生成细胞的病理转变。由于 NO 产生受到抑制，细胞表现出血管舒张受损、血栓形成增加和细胞修复能力丧失。年龄、高血压、高脂血症、创伤后应激障碍和吸烟等心血管危险因素会诱发炎症信号，从而刺激这种病理转变。内皮功能障碍的一种表现是糖尿病和外周动脉疾病患者中出现的慢性溃疡性伤口。我们国家的退伍军人面临慢性溃疡性伤口的高风险，因为他们具有许多此类心脏危险因素。该退伍军人管理局职业发展奖（CDA-2）的构思前提是光能产生一种新的方法来增加内皮功能障碍所清除的一氧化氮，并且在未来可能会导致针对改善伤口愈合的新型血管疗法的开发。这些研究旨在检验光能可以特异性释放 NO 的假设 缺血组织。这种 NO 的替代来源有可能改善 NO 产生减弱区域的内皮功能，从而改善血管反应性和伤口愈合。我们的假设将通过针对已知产生和结合 NO 的一组确定的蛋白质进行测试，并在能量暴露之前和之后测量其产生。我们还将测量生理条件和炎症应激下能量对刺激血管舒张和伤口愈合的影响。从这项研究中获得的信息将扩大我们对细胞中重要的一氧化氮储存的位置的理解，以及能量如何刺激这些储存以改善炎症性疾病中的内皮细胞稳态。