Biology and Novel Therapeutics of Cardiovascular Peptides

描述(由申请人提供)： 我们计划项目修订申请的中心主题仍然是加快我们的努力，将内源性颗粒鸟苷环化酶(GC)激活剂、利钠肽(NPs)的生物学转化为与心力衰竭和高血压高度相关的人类心脏肾脏疾病的新疗法。这是由NPs及其与3‘，5’环鸟苷一磷酸(CGMP)相连的GC受体的生物学、治疗学和诊断学所推动的。事实上，在分子或细胞水平上的研究，在小鼠或大型动物模型中，在正常人或患有心血管或肾脏疾病的人类的药理学或生理学研究中，以及在最近的人类对NP基因变体的研究中，都提供了一种具有广泛有益的多效性作用的体液系统的观点。NP/GC/cGMP信号的这些有益特性包括利钠、血管扩张、正性促性腺激素、抑制心肌细胞凋亡和肥大、抑制成纤维细胞增殖和胶原合成、抑制醛固酮和诱导血管再生。事实上，这些cGMP介导的与NPs相关的GC受体激活特性为新药发现提供了前所未有的机会。每个项目的亮点如下：项目1：在实验性舒张性心力衰竭中利用新的基因递送策略通过GC-A受体的慢性过度表达来增强心肌细胞功能(玛格丽特·雷德菲尔德MD-项目负责人)；项目2：推进设计的NP CD-NP在人类中的口服递送的开发，并开发第二种针对心脏肾脏疾病的新型GC-A/-B激活剂(小John C Burnett Jr.，MD-项目负责人)；项目3：在患有收缩和舒张期临床前心力衰竭并伴有肾功能受损的患者中，建立优化NP/PDEV/cGMP途径、慢性PDEV抑制和慢性新型GC-A激活的协同作用(黄陈博士-项目负责人)。因此，这一应用程序汇集了一个高度合作的内科科学家团队，他们提出了一个高度翻译的建议，应该会导致心肾疾病的创新疗法。

DESCRIPTION (PROVIDED BY APPLICANT): Our Central Theme of this Program Project revised application continues to be to accelerate our efforts to translate the biology of the endogenous particulate guanylyl cyclase (GC) activators, the natriuretic peptides (NPs), into novel therapeutics for human cardiorenal disease highly relevant to heart failure and hypertension. This is motivated by the biology, therapeutics and diagnostics of the NPs and their GC receptors linked to 3',5' cyclic guanosine monophosphate (cGMP). Indeed, studies at the molecular or cell level, in murine or large animal models, in pharmacologic or physiologic studies in normal or humans with cardiovascular or renal disease and in recent human of NP gene variants have provided a view of a humoral system with broad beneficial pleiotropic actions. These beneficial properties of NP/GC/cGMP signaling include natriuresis, vasodilatation, positive lusitropism, inhibition of myocyte apoptosis and hypertrophy, inhibition of fibroblast proliferation and collagen synthesis, suppression of aldosterone and induction of vascular regeneration. Indeed, these cGMP-mediated properties of GC receptor activation linked to the NPs represent an unprecedented opportunity for novel drug discovery. Highlights of each Project are as follows: Project 1: Enhance cardiomyocyte function through chronic overexpression of the GC-A receptor utilizing a novel gene delivery strategy in experimental diastolic heart failure (Margaret Redfield MD - Project Leader); Project 2: Advance the development of oral delivery in humans of the designer NP CD-NP and the development of a second novel GC-A/-B activator individualized for cardiorenal disease (John C Burnett Jr., MD - Project Leader); Project 3: Establish in humans with systolic and diastolic preclinical heart failure with impaired renal function the synergistic action of optimizing the NP/PDEV/cGMP pathway with chronic PDEV inhibition with chronic novel GC-A activation (Dr. Horng Chen MD - Project Leader). Thus, this application brings together a highly collaborative team of physician-scientists with a highly translational proposal which should lead to innovative therapeutics for cardiorenal disease.