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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.

总结