Therapeutic Reversal of Endothelial Dysfunction in Atherogenesis

治疗性逆转动脉粥样硬化形成中的内皮功能障碍

• 批准号: 9141224
• 负责人: William James Adams
• 金额: $ 85.73万
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9141224
• 关键词: Adverse event; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Area; Arterial Fatty Streak; Atherosclerosis; Biological; Biological Assay; Blood Pressure; Blood Vessels; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell physiology; Cells; Chemicals; Chemistry; Cholesterol; Chronic; Clinical; Development; Diabetes Mellitus; Disease; Drug Kinetics; Endothelium; Environment; Evaluation; Event; Funding; Gene Proteins; Goals; Hypertension; Individual; Inflammation; Inflammatory; Investments; Laboratories; Lead; Lesion; Life; Location; Metabolism; Molecular Target; Morbidity - disease rate; Mus; Myocardial Infarction; Oral; Patients; Peripheral arterial disease; Pharmaceutical Chemistry; Pharmacologic Substance; Phase; Phenotype; Population; Proteins; RNA interference screen; Relaxation; Resistance; Risk Factors; Series; Signal Transduction; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Specificity; Stroke; Therapeutic; Tissues; Toxicology; Translating; Translations; Vascular Endothelial Cell; Vascular Endothelium; Work; atherogenesis; atheroprotective; base; cardiovascular disorder therapy; cardiovascular risk factor; drug discovery; endothelial dysfunction; hemodynamics; hypercholesterolemia; in vivo; innovation; insight; mortality; mouse model; novel; novel strategies; novel therapeutic intervention; pre-clinical; preclinical efficacy; programs; protective effect; public health relevance; response; small molecule; therapeutic target; transcription factor; treatment strategy

 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.

 描述(申请人提供)：动脉粥样硬化血管内皮细胞功能障碍的治疗逆转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，与高胆固醇水平、高血压和糖尿病等风险因素密切相关。针对这些系统性风险因素，有有效的商业可用的治疗方法。然而，尽管如此，服用这些治疗性药物的患者仍然有相当高的不良事件发生率，而且即使在没有这些传统的系统性危险因素的情况下，也有相当一部分人遭受不良心血管事件。重要的是，面对这些全身性的经典心血管危险因素，动脉血管的某些区域仍然相对抵抗动脉粥样硬化病变的发展，而一些区域则相对易感。有趣的是， 这些“受保护的”和“易受影响的”区域的解剖位置在个体之间甚至在物种之间是可以预测的。多条证据表明，这些动脉区域内特定的血流动力学环境对局部血管内皮细胞产生保护作用，从而抑制早期病变的发展。相反，血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。尽管对血流动力学引起的“动脉粥样硬化保护”和“动脉粥样硬化易感性”的某些生物学机制的理解最近取得了进展，但这些基本发现尚未转化为治疗心血管疾病的策略。在我们STTR资助的项目的第一阶段，我们利用对血管内皮细胞对血流动力学反应的潜在机制的见解，建立了一个新的心血管药物发现平台，从而识别出能够模拟血流动力学诱导的动脉粥样硬化保护的新化学实体。在这个二期项目中，我们将继续开发这些有希望的成果。在这里，我们的主要目标是1)从我们现有的血管保护化合物系列中开发一种优化的铅化合物，2)表征这种血管保护化合物的作用机制，以及3)在动脉粥样硬化的动物模型中评估这种优化的铅的临床前疗效。这些重要的里程碑将催化这一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。