Novel Therapeutics for Endothelial Dysfunction

总结 内皮功能障碍是许多微血管和大血管疾病的部分原因，这些疾病可导致 严重的发病率和死亡率。它是血管细胞之间复杂相互作用的结果， 内皮细胞、周细胞、平滑肌细胞和免疫细胞，并且其特征在于血流动力学 变化、微循环障碍以及血流和代谢需求之间的解偶联。的 多种疾病的发展，包括高血压、心肌梗塞、中风、先兆子痫， 肺动脉高压、糖尿病性溃疡和终末器官损害，都可以部分归因于血管性 这些疾病中的每一种每年仅在美国就造成数十亿美元的医疗费用。虽然 更好的护理改善了内皮功能障碍相关疾病患者的生存率， 现有的药物不能预防大量患者中内皮功能障碍的进展， 这可能是由于缺乏能够积极改善内皮功能的治疗剂。显然，小说 非常需要能够积极改善血管功能的策略。最近的进展表明， 一组血管受体，RAMP/RAMP受体及其配体的信号传导对于血管生成是必需的。 在胚胎发生和整个成年期的发育。一致地，受体配体已经被 显示改善血管生成、血管生成和内皮屏障功能，并防止血液动力学 动物的烦恼重要的是，我们最近发现了一组长效超级激动剂， 有效地激活多种RAMP/RAMP受体。因此，我们建议开发一种基于 这些新发明的超激动剂，以改善患者的血流和血管顺应性， 内皮功能障碍相关疾病。在这个概念验证研究中，我们将进一步评估这个系列 以优化其体内药代动力学和药效学特征，并确定 目标1中最有效的候选药物。在目标2中，我们将研究疗效并确定最有效的 用于治疗自发性高血压和心脏肥大的所选铅类似物的剂量 大鼠所提出的治疗代表了一种新的药理学方法，专门针对一组 血管受体，并降低内皮功能障碍相关的死亡率和发病率 病因学成功完成第一阶段SBIR提案将为我们提供所需的关键信息， 为进一步的临床前开发选择新的候选药物。

Summary Endothelial dysfunction is part of the causes of many micro and macrovascular diseases that can lead to serious morbidity and mortality. It is a result of complex interactions between vascular cells including endothelial cells, pericytes, smooth muscle cells and immune cells, and is characterized by hemodynamic changes, microcirculatory disturbances, and uncoupling between blood flow and metabolic requirements. The development of a variety of diseases, including hypertension, myocardial infarction, stroke, preeclampsia, pulmonary arterial hypertension, diabetic ulcer, and end-organ damages, can all be partly attributed to vascular dysfunction, and each of these diseases incurs billions in health cost each year in the US alone. Although better care has improved the survival of patients with endothelial dysfunction-associated diseases, the progression of endothelial dysfunction in a large population of patients cannot be prevented by existing drugs, perhaps due to the lack of therapeutics that can actively improve endothelial functions. Clearly, novel strategies that can actively improve vascular functions are much needed. Recent advances have shown that the signaling of a group of vascular receptors, CLR/RAMP receptors, and their ligands is essential for vascular development during embryogenesis and throughout adulthood. Consistently, the receptor ligands have been shown to improve angiogenesis, vasculogenesis and endothelial barrier functions, and prevent hemodynamic disturbances in animals. Importantly, we have recently discovered a group of long-acting superagonists that potently activate multiple CLR/RAMP receptors. Accordingly, we propose to develop a hormonal therapy based on these newly invented superagonists to improve blood flow and vascular compliance in patients with endothelial dysfunction-associated diseases. In this proof-of-concept study, we will evaluate further this series of compounds to optimize their pharmacokinetic and pharmacodynamic characteristics in vivo, and identify the most potent drug candidate in Aim 1. In Aim 2, we will investigate the efficacy and identify the most efficacious dose of the selected lead analog for the treatment of spontaneous hypertension and cardiac hypertrophy in rats. The proposed therapy represents a novel pharmacological approach to specifically target a group of vascular receptors, and to reduce the mortality and morbidity resulting from endothelial dysfunction-associated etiology. Successful completion of this Phase I SBIR proposal will provide us with critical information needed to select a novel drug candidate for further preclinical development.