Biology and Therapeutics of Cardiovascular Peptides

描述（由申请人提供）： 该计划的中心主题是推进利钠肽系统（BNP）的生物学，从而为心血管疾病提供创新的治疗策略。我们的工作假设是利钠肽（NPs）（ANT和BNP与颗粒鸟苷酸环化酶（pGC）利钠肽A受体[NPR-A]结合，CNP与pGC NPR-B受体结合，均通过cGMP发挥作用）起自分泌作用，旁分泌和循环因子，其生物学特性介导对心血管功能和结构的保护作用，以补充对肾脏的已知作用，脉管系统这为进一步开发其作为治疗心血管疾病的新型治疗剂提供了理论基础。四个项目提出了两个核心，涉及分子和细胞生物学，小鼠和大动物综合生理学，细胞和基因治疗和基于人类生理学的综合临床研究中心（GCRC）。项目1提出了一个深入的应用整合生理学在新型小鼠模型的基因修饰的利钠肽（NP）受体功能，以促进我们的理解，其生理和治疗潜力的心肌细胞结构和功能的调制。这里特别强调NPR-A受体调节舒张功能，适用于舒张性心力衰竭的治疗。项目2定义了使用天然和合成马约设计的NP进行慢性NP治疗的有效和新型策略，以预防高血压性心脏病（HHD）临床相关大型动物模型中的心脏纤维化，以及采用不依赖于一氧化氮的新型sGC刺激剂靶向可溶性GC的替代cGMP策略。此外，NPs和cGMP抑制心脏成纤维细胞增殖的机制将得到阐明。项目3从项目1和2的HHD转移到CHF的大型动物模型，开发细胞和基因治疗策略以延迟CHF的进展。虽然BNP的NP疗法已被批准用于人类急性CHF，但优先考虑的是应用新技术来定义心血管疾病中的长期肽递送。在项目4中，重要的是将我们基于实验室的研究扩展到对NP治疗人类疾病的生理学和治疗潜力的理解，重点是BNP治疗。

DESCRIPTION (provided by applicant): The Central Theme of this program is to advance biology of the Natriuretic Peptide System (NPS) leading to innovative therapeutic strategies for cardiovascular disease. Our working hypothesis is that the natriuretic peptides (NPs) (ANT and BNP which bind to the particulate guanylyl cyclase (pGC) natriuretic peptide A receptor [NPR-A] and CNP which binds to the pGC NPR-B receptor and which all function via cGMP) serve as autocrine, paracrine and circulating factors whose biological properties mediate protective actions upon cardiovascular function and structure to complement known actions on the kidney and vasculature. This provides the rationale for their further development as novel therapeutic agents for the treatment of cardiovascular disease. Four projects are proposed with 2 cores and involve molecular and cell biology, mouse and large animal integrative physiology, cell and gene therapy and General Clinical Research Center (GCRC) based human physiology. Project 1 proposes an in-depth application of integrative physiology in novel mouse models of genetically modified natriuretic peptide (NP) receptor function to advance our understanding of the NPS and its physiologic and therapeutic potential in the modulation of cardiomyocyte structure and function. Here there is special emphasis on NPR-A receptor regulation of diastolic function with applicability to the therapeutics of diastolic heart failure. Project 2 defines an effective and novel strategy of chronic NP therapy with native and synthetic Mayo designed NPs to prevent cardiac fibrosis in a clinically relevant large animal model of hypertensive heart disease (HHD) as well as pursuing an alternative cGMP strategy targeting soluble GC with a novel sGC stimulator not dependent upon Nitric Oxide. In addition, the mechanism by which the NPs and cGMP inhibit cardiac fibroblast proliferation will be elucidated. Project 3 shifts from HHD in Projects 1 and 2 to a large animal model of CHF developing a strategy of cell and gene therapy to delay the progression of CHF. While NP therapy with BNP has been approved in humans for acute CHF, a high priority is to apply new technologies to define long-term peptide delivery in cardiovascular disease. In Project 4, importantly extends our laboratory-based research to the understanding of the physiology and therapeutic potential of the NPs to the treatment of human disease, focusing on BNP therapy.