Cardiac Peptides in Cardiorenal Protection

描述（由申请人提供）：充血性心力衰竭（CHF）是一种主要的健康负担，因此需要了解疾病进展，以制定治疗、诊断和预防策略。越来越多的证据表明，肾脏以及心脏在CHF中起着核心作用。这一高度转化应用的目的是定义在人类和实验性CHF中控制心肾稳态的心脏和肾脏之间受损联系的机制，并促进心肾保护的新型治疗和创新诊断。我们广泛的工作假设是连接心脏和肾脏的GC/cGMP通路的缺陷是CHF中肾和心脏功能受损的关键机制。我们还假设，心肾功能障碍可以克服创新的GC/cGMP为基础的治疗，并获得的知识也将导致新的诊断CHF。目的1：证实proBNP是一种由正常人心脏分泌的循环激素，在循环中被加工成成熟的BNP。确定corin对循环proBNP的加工在CHF中受损。目标二：确定proBNP是BNP的上级分子形式，可作为检测心室功能障碍的生物标志物和不良心血管结局的预后生物标志物。确定BNP遗传变异rs 198389影响一般社区中的循环proBNP，并且基于BNP的最佳生物标志物策略将proBNP测量与rs 198389基因分型相结合。目标3：确定在改善CHF和肾功能受损患者的心肾功能方面，使用马约设计的嵌合NP（CD-NP）进行GC-A/GC-B双重活化上级优于单独使用GC-A活化和BNP。在人肾小球细胞中，与单独GC-A与BNP和单独GC-B与CNP相比，确定CD-NP双重GC-A/GC-B刺激的综合cGMP激活特性。最后，确定CD-NP对DNP C-末端的存在继发于人NEP的蛋白酶降解具有高度抗性。目标4：在进行性CHF模型中，与单独使用BNP的GC-A激活相比，使用CD-NP的慢性GC-A/GC-B激活可延迟CHF进展。 公共卫生相关性：心脏和肾脏中的一系列激素将这两个器官联系起来，有助于流体容量和血压的最佳调节。在对心脏的应激反应中，这些激素起着保护心脏和肾脏功能的作用，但当心力衰竭严重时，该系统可能有缺陷。我们的提案旨在更好地了解这种激素心脏和肾脏的联系，从而为人类心力衰竭提供新型药物和诊断方法。

DESCRIPTION (provided by applicant): Congestive heart failure (CHF) is a leading health burden for which there is an unmet need for understanding disease progression in order to develop therapeutic, diagnostic and preventative strategies. Increasing evidence has demonstrated that the kidney as well as the heart plays a central role in CHF. The objective of this highly translational application is to define mechanisms of an impaired link between the heart and kidney in the control of cardiorenal homeostasis in human and experimental CHF and to promote novel therapeutics and innovative diagnostics for cardiorenal protection. Our broad working hypothesis is that a defect in the GC/cGMP pathway which links the heart and kidney is a key mechanism of impaired renal and cardiac function in CHF. We also hypothesize that cardiorenal dysfunction can be overcome with innovative GC/cGMP-based therapeutics and that knowledge gained will also lead to novel diagnostics for CHF. Aim 1: Establish that proBNP is a circulating hormone secreted by the normal human heart that is processed to mature BNP in the circulation. Establish that the processing of circulating proBNP by corin is impaired in CHF. Aim 2: Establish that proBNP is the superior molecular form of BNP to serve as a biomarker for the detection of ventricular dysfunction and as a prognostic biomarker for adverse cardiovascular outcomes. Establish that the BNP genetic variant rs198389 affects circulating proBNP in the general community and that the optimal BNP-based biomarker strategy integrates measurement of proBNP with genotyping for rs198389. Aim 3: Establish that dual GC-A/GC-B activation with a Mayo designed chimeric NP (CD-NP) is superior to GC-A activation alone with BNP in improving cardiorenal function in humans with CHF and impaired renal function. Establish the comprehensive cGMP activating properties of dual GC-A/GC-B stimulation with CD-NP as compared to GC-A alone with BNP and GC-B alone with CNP in human renal glomerular cells. Finally, establish that CD-NP is highly resistant to protease degradation by human NEP secondary to the presence of the C-terminus of DNP. Aim 4: Establish that CHF progression can be delayed with chronic GC-A/GC-B activation with CD-NP compared to GC-A activation with BNP alone in a model of progressive CHF. PUBLIC HEALTH RELEVANCE: A family of hormones in the heart and kidney link these two organs that contribute to the optimal regulation of fluid volume and blood pressure. In response to stress to the heart these hormones function to preserve heart and kidney function but when heart failure is severe this system may be defective. Our proposal seeks to better understand this hormonal heart and kidney connection leading to novel new drugs and diagnostics for human heart failure.