Pharmacological Targeting of Endothelial Dysfunction in Atherogenesis

动脉粥样硬化形成中内皮功能障碍的药理学靶向

• 批准号: 8719164
• 负责人: William James Adams
• 金额: $ 29.29万
• 依托单位: RIPARIAN PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719164
• 关键词: Adverse event; Arterial Fatty Streak; Atherosclerosis; Biological; Biological Assay; Biomechanics; Biomedical Engineering; Blood Pressure; Blood Vessels; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cholesterol; Chronic; Data; Development; Diabetes Mellitus; Disease; Drug Targeting; Effectiveness; Endothelium; Epidemic; Event; Foundations; Genes; Goals; Hypertension; Individual; Inflammation; Inflammatory; Intervention; Knowledge; Lead; Lesion; Life; Location; Molecular Target; Morbidity - disease rate; Myocardial Infarction; Patients; Peripheral arterial disease; Phenotype; Population; Reporter; Resistance; Risk Factors; Signal Pathway; Stroke; System; Technology; Therapeutic; Translating; Translational Research; United States; Use Effectiveness; Vascular Endothelium; atherogenesis; atheroprotective; base; cardiovascular risk factor; drug development; drug discovery; endothelial dysfunction; hemodynamics; hypercholesterolemia; improved; in vitro Model; innovation; insight; mortality; novel; novel strategies; programs; public health relevance; response; small molecule; small molecule libraries; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Pharmacological Targeting of Endothelial Dysfunction in Atherogenesis Cardiovascular disease is the leading cause of morbidity and mortality in the United States and is an emerging epidemic world-wide. In particular, atherosclerosis is a life-threatening disease strongly associated with risk factors such as elevated cholesterol levels, high blood pressure and diabetes. There are effective commercially available therapeutics that target these systemic risk factors. However, despite these advances, there is still a significant rate of adverse events in patients prescribed these therapeutics and a significant population that suffer adverse cardiovascular events in the absence of these conventional systemic risk factors. Importantly, in the face of potent systemic classical cardiovascular risk factors, certain regions of the arterial vasculature remain relatively resistant to the development of atherosclerotic lesions while some are relatively susceptible. Interestingly, the anatomical locations of these "protected" and "susceptible" regions are predictable between individuals and even between species. Multiple lines of evidence suggest that the specific hemodynamic conditions within these arterial regions exert a protective influence on the local vascular endothelium, and thus inhibit early lesion development. In contrast, hemodynamic conditions present in other regions of the vasculature evoke a pro-inflammatory pro-atherogenic dysfunctional state in the endothelium. Despite recent progress in the understanding of some of the biological mechanisms responsible for hemodynamics-induced "atheroprotection" and "atherosusceptibility," these basic discoveries have not yet been translated into therapeutic strategies for the treatment of cardiovascular disease. In this project, the insights recently gained into the mechanisms underlying endothelial responses to hemodynamic flow will be used to establish a novel cardiovascular drug discovery platform. The major goals are to 1) discover small molecules able to induce the expression of atheroprotective genes in the context of pathological hemodynamic conditions, 2) identify potential drug targets that are critical for hemodynamics-induced atherosusceptibility, and 3) validate the effectiveness of using small molecules to improve endothelial function using several in vitro models of endothelial activation and inflammation. The knowledge generated by this project should establish a novel cardiovascular drug discovery effort targeting endothelial dysfunction, an unexplored but critical "local risk factor" for atherosclerosis.

描述（由申请人提供）：动脉粥样硬化形成中内皮功能障碍的药理学靶向心血管疾病是美国发病率和死亡率的主要原因，并且是世界范围内的新兴流行病。特别是，动脉粥样硬化是一种危及生命的疾病，与胆固醇水平升高、高血压和糖尿病等危险因素密切相关。有针对这些系统性危险因素的有效市售疗法。然而，尽管取得了这些进展，但在接受这些治疗的患者中，不良事件的发生率仍然很高，而且在没有这些传统的系统性危险因素的情况下，有相当多的人群会遭受不良心血管事件。重要的是，面对强大的全身性经典心血管危险因素，动脉脉管系统的某些区域对动脉粥样硬化病变的发展仍然具有相对抵抗力，而有些区域则相对容易受到影响。有趣的是，这些“受保护”和“易感”区域的解剖位置在个体之间甚至物种之间是可以预测的。多种证据表明，这些动脉区域内的特定血流动力学条件对局部血管内皮产生保护性影响，从而抑制早期病变的发展。相反，脉管系统其他区域的血流动力学状况会引起内皮细胞的促炎、促动脉粥样硬化功能障碍状态。尽管最近在理解血流动力学诱导的“动脉粥样硬化保护”和“动脉粥样硬化易感性”的一些生物学机制方面取得了进展，但这些基本发现尚未转化为治疗心血管疾病的治疗策略。在这个项目中，最近获得的关于内皮细胞对血流动力学反应的机制的见解将用于建立一个新型的心血管药物发现平台。主要目标是 1) 发现能够在病理血流动力学条件下诱导动脉粥样硬化保护基因表达的小分子，2) 确定对血流动力学诱导的动脉粥样硬化易感性至关重要的潜在药物靶点，以及 3) 验证使用小分子的有效性使用几种内皮激活和炎症的体外模型来改善内皮功能的分子。该项目产生的知识应该建立一种针对内皮功能障碍的新型心血管药物发现工作，内皮功能障碍是动脉粥样硬化的一种未经探索但至关重要的“局部危险因素”。