Novel Therapeutics for Endothelial Dysfunction

内皮功能障碍的新疗法

基本信息

批准号：
9253486
负责人：
SHEAU-YU Teddy HSU
金额：
$ 29.04万
依托单位：
ADEPTHERA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9253486
关键词：
Adrenergic beta-Antagonists Adult Age Agonist Allopurinol Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Animal Model Animals Antihypertensive Agents Atherosclerosis Blood Vessels Blood flow Calcium Channel Cardiovascular Diseases Caring Cells Cerebral Infarction Characteristics Clinical Complex Contracts Coronary Arteriosclerosis Coronary heart disease Data Development Diabetes Mellitus Diabetic ulcer Disease Disease Progression Diuretics Dose Drug Kinetics Edema Embryonic Development Endothelial Cells Endothelin Endothelium Etiology Event Exhibits Extravasation Health Care Costs Healthcare Systems Heart Hypertrophy Hormones Human Hyperlipidemia Hypertension Immune Impairment Inbred SHR Rats Individual Ischemia Kidney Lead Left Ventricular Hypertrophy Life Ligands Melanocyte stimulating hormone Metabolic Metformin Methods Mineralocorticoid Receptor Morbidity - disease rate Myocardial Infarction Nitric Oxide Organ Oxidative Stress Patient-Focused Outcomes Patients Pericytes Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Plasminogen Activator Platelet Activation Platelet Aggregation Inhibition Play Pre-Eclampsia Production RAMP1 Rattus Receptor Activation Receptor Signaling Regulation Risk Factors Role Series Signal Transduction Small Business Innovation Research Grant Smoking Smooth Muscle Myocytes Stroke Therapeutic Thrombosis Vascular Diseases Vascular Endothelium adrenomedullin analog angiogenesis base burden of illness calcitonin receptor-like receptor clinical development clinically significant disease natural history drug candidate endothelial dysfunction hemodynamics hormone therapy improved improved outcome in vivo interest macrovascular disease mortality novel novel strategies novel therapeutics patient population preclinical development prevent pulmonary arterial hypertension receptor receptor-activity-modifying protein therapeutic candidate vascular smooth muscle cell proliferation vasculogenesis vasoconstriction xanthine oxidase inhibitor

项目摘要

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.

概括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。这是血管细胞之间复杂相互作用的结果，包括内皮细胞、周细胞、平滑肌细胞和免疫细胞，并以血流动力学为特征变化、微循环障碍以及血流和代谢需求之间的脱钩。这多种疾病的发生，包括高血压、心肌梗塞、中风、先兆子痫、肺动脉高压、糖尿病溃疡和终末器官损伤都可以部分归因于血管仅在美国，每种疾病每年都会造成数十亿美元的健康成本。虽然更好的护理提高了内皮功能障碍相关疾病患者的生存率现有药物无法阻止大量患者内皮功能障碍的进展，也许是由于缺乏可以积极改善内皮功能的治疗方法。显然，新颖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、CLR/RAMP 受体及其配体的信号传导对于血管生成至关重要胚胎发生期间和整个成年期的发育。一致地，受体配体已被显示可改善血管生成、血管发生和内皮屏障功能，并防止血流动力学改变对动物的干扰。重要的是，我们最近发现了一组长效超级激动剂，有效激活多个 CLR/RAMP 受体。因此，我们建议开发一种基于激素疗法这些新发明的超级激动剂可改善患者的血流量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，我们将进一步评估该系列化合物，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，我们将研究功效并确定最有效的药物所选先导类似物治疗自发性高血压和心脏肥大的剂量老鼠。所提出的疗法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选择一种新的候选药物进行进一步的临床前开发。