Therapeutic Reversal of Endothelial Dysfunction in Atherogenesis

 描述（由申请方提供）：动脉粥样硬化中内皮功能障碍的治疗性抑制心血管疾病是世界上发病率和死亡率的主要原因。特别是，动脉粥样硬化是一种威胁生命的疾病，与胆固醇水平升高、高血压和糖尿病等风险因素密切相关。有针对这些全身性风险因素的有效的市售治疗剂。然而，尽管有这些，仍然有一个显着的不良事件发生率在患者处方这些治疗和显着的人口遭受不良心血管事件，即使在没有这些传统的全身性风险因素。重要的是，面对这些全身性的经典心血管危险因素，动脉血管系统的某些区域对动脉粥样硬化病变的发展保持相对抵抗力，而一些区域相对易感。有趣的是， 这些“受保护的”和“易受影响的”区域的解剖学位置在个体之间甚至在物种之间是可预测的。多种证据表明，这些动脉区域内的特定血流动力学环境对局部血管内皮产生保护性影响，从而抑制早期病变发展。相比之下，脉管系统的其他区域中存在的血液动力学状况引起内皮中的促炎促动脉粥样硬化功能障碍状态。尽管最近在理解血液动力学诱导的“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用于治疗心血管疾病的治疗策略。在我们STTR资助项目的I期，我们利用关于内皮对血流动力学流动的反应机制的见解建立了一个新的心血管药物发现平台，从而鉴定出能够模拟血流动力学诱导的动脉粥样硬化保护作用的新型化学实体。在这个第二阶段的项目中，我们将继续开发这些有希望的结果。在这里，主要目标是1）从我们现有的血管保护化学系列中开发一种优化的先导化合物，2）表征这种血管保护化合物的作用机制，以及3）评估这种优化的先导化合物在动物模型中的临床前功效动脉粥样硬化。这些重要的里程碑应该促进这种创新的心血管药物发现努力向临床转化，从而建立一种新的心血管疾病治疗方法。

 DESCRIPTION (provided by applicant): Therapeutic Reversal of Endothelial Dysfunction in Atherogenesis Cardiovascular disease is the leading cause of morbidity and mortality in the world. 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. Yet despite these, there is still a significant rate of adverse events in patients prescribed these therapeutic and a significant population that suffer adverse cardiovascular events even in the absence of these conventional systemic risk factors. Importantly, in the face of these systemic classical cardiovascular risk factors, certain regions of the arterial vasculature remain relatively resistan 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 environments 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. During the Phase I of our STTR funded project, we utilized insights regarding the mechanisms underlying endothelial responses to hemodynamic flow to establish a novel cardiovascular drug discovery platform, which resulted in the identification of novel chemical entities able to mimic hemodynamics-induced atheroprotection. In this Phase II project, we will continue development of these promising results. Here, the major goals are to 1) develop an optimized lead compound from our existing vasoprotective chemical series, 2) characterize the mechanism of action of this vasoprotective compound, and 3) evaluate the preclinical efficacy of this optimized lead in an animal model of atherosclerosis. These essential milestones should catalyze this innovative cardiovascular drug discovery effort toward clinical translation, thus establishing a new approach to cardiovascular disease therapy.