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，对了解疾病进展以制定治疗、诊断和预防策略的需求尚未得到满足。越来越多的证据表明，肾脏和心脏在CHF中起着核心作用。这一高度翻译应用的目的是确定在人类和实验性CHF中心脏和肾脏之间受损的联系在控制心肾稳态中的机制，并促进用于心肾保护的新疗法和创新诊断技术。我们广泛的工作假设是，连接心脏和肾脏的GC/cGMP途径的缺陷是CHF患者肾和心功能受损的关键机制。我们还假设，心肾功能障碍可以通过基于GC/cGMP的创新疗法来克服，所获得的知识也将导致对CHF的新诊断。目的1：建立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CHF时Corin对循环proBNP的处理受损。目的2：确定ProBNP是BNP的高级分子形式，可作为检测心功能不全的生物标志物和预测心血管不良结局的生物标志物。确定BNP基因变异rs198389影响一般社区中循环中的proBNP，并确定基于BNP的最佳生物标记物策略将proBNP的测量与rs198389的基因分型相结合。目的：建立GC-A/GC-B双重激活与Mayo设计的嵌合NP(CD-NP)在改善CHF和肾功能受损患者的心肾功能方面优于GC-A和BNP单独激活。在人肾小球细胞中，建立CD-NP对GC-A/GC-B双重刺激与GC-A单独刺激BNP和GC-B单独刺激CNP的综合cGMP激活特性。最后，证明CD-NP高度抵抗人NEP对蛋白酶的降解，其次是DNP的C-末端的存在。目的：在进展性心力衰竭模型中，建立慢性激活GC-A/GC-B与单用BNP激活GC-A相比，CD-NP可延缓慢性GC-A/GC-B的进展。 与公共健康相关：心脏和肾脏中的一系列荷尔蒙将这两个器官联系在一起，有助于优化体液量和血压的调节。作为对心脏压力的反应，这些激素起到保护心脏和肾脏功能的作用，但当心力衰竭严重时，这一系统可能是有缺陷的。我们的建议旨在更好地了解这种荷尔蒙、心脏和肾脏的联系，从而为人类心力衰竭提供新的药物和诊断方法。

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.