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

小分子 NO 前体作为血管舒张和血管生成中 NO 的生物活性来源

基本信息

批准号：
10406907
负责人：
Nicole Lohr
金额：
$ 44.98万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10406907
关键词：
Acute Affect Age American Amputation Animal Model Ankle Arteries Biochemical Blood Blood Vessels Blood flow Cardiovascular system Cell Culture Techniques Cells Characteristics Chemicals Chronic Clinical Clinical Trials Data Diabetes Mellitus Disease Electromagnetics Endothelial Cells Endothelium Enzymes Exercise Exposure to Gastrocnemius Muscle Growth Health Care Costs Health system Hindlimb Home Hospitalization Human Hyperlipidemia Hypotension Impairment Iron Ischemia Isolated limb perfusion Knowledge Lasers Leg Light Measures Mediator of activation protein Medical Medicare Metabolic Morbidity - disease rate Muscle NOS3 gene Nature Nitric Oxide Nitric Oxide Donors Nitric Oxide Synthase Obstruction Operative Surgical Procedures Pain Patients Penetration Perfusion Peripheral Peripheral arterial disease Pharmaceutical Preparations Phototherapy Physiological Production Quality of life Recovery Relaxation S-Nitrosothiols Signal Transduction Site Skeletal Muscle Skin Skin Temperature Smoking Source Sulfhydryl Compounds Surface Testing Time Tissues Translating Vasodilation Vasodilator Agents ameroid angiogenesis arteriole autocrine base chronic pain patient chronic wound clinically relevant cost design dinitrosyl iron complex effective therapy endothelial dysfunction experience human subject improved in vivo indexing ineffective therapies inflammatory milieu irradiation limb ischemia mortality mouse model myocardial infarct sizing novel strategies pre-clinical prevent side effect small molecule success symptom treatment traditional therapy treatment center trend

项目摘要

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.

该应用程序是基于某些疾病的前提。周围动脉疾病（PAD），传统疗法在症状和相关治疗方面无效病态。目前，PAD会影响超过800万美国人，并将影响更多国家年龄。治疗受试者的医疗保健费用很大（每年40亿美元 Medicare），大多数患者需要大量的血管内和外科手术包括截肢。医疗疗法未能影响这种成本和功效曲线的趋势。该提议试图通过认识到归因的内皮功能障碍来改变此范式垫可防止适当的血流恢复（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损。我们有在血液和组织中发现的一氧化氮（NO）前体是由红光能刺激的释放不释放并产生稳定的无结合血管扩张剂。此外，发布此版本在没有一氧化氮合酶（NOS）的情况下，自分泌因子会扩张动脉/动脉。这红光的作用在临床上是相关的，因为我们已经确定了血流的显着升高当健康受试者和PAD患者的胃肌肌肉暴露于红色时光。本应用程序中的方法是评估这些铁和硫醇的影响没有使用生化和细胞培养技术的前体，可以优化鼠的光递送亚急性后肢缺血的模型（以模仿临床垫），并确认我们在人类中的发现带有垫子的受试者。我们希望收集的数据将确定否细胞内无前体分子可以增加，改善内皮功能障碍和增强肢体灌注。