Biology and Therapeutics of Cardiovascular Peptides

描述(由申请人提供)： 该计划的中心主题是促进钠尿肽系统(NPS)生物学的发展，从而导致心血管疾病的创新治疗策略。我们的工作假设是，利钠肽(NPs)(ANT和BNP与颗粒鸟苷环酶(PGC)钠尿肽A受体[NPR-A]结合，CNP与PGC NPR-B受体结合，均通过cGMP发挥作用)作为自分泌、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，以补充对肾脏和血管的已知作用。这为它们进一步发展成为治疗心血管疾病的新型治疗药物提供了理论基础。提出了四个两个核心的项目，涉及分子和细胞生物学、小鼠和大动物综合生理学、细胞和基因治疗以及以普通临床研究中心(GCRC)为基础的人类生理学。项目1提出了在转基因钠尿肽(NP)受体功能的新型小鼠模型中深入应用综合生理学，以促进我们对NPS及其在调节心肌细胞结构和功能中的生理和治疗潜力的理解。这里特别强调NPR-A受体对舒张期功能的调节，并适用于舒张性心力衰竭的治疗。项目2定义了一种有效的新的慢性NP治疗策略，使用本地和合成的Mayo设计的NPs来预防临床相关的高血压心脏病(HHD)大动物模型的心脏纤维化，并寻求另一种针对可溶性GC的cGMP策略，该策略具有不依赖于一氧化氮的新型sGC刺激物。此外，还将阐明NPs和cGMP抑制心脏成纤维细胞增殖的机制。项目3从项目1和项目2中的HHD转移到CHF的大型动物模型，开发出一种延缓CHF进展的细胞和基因治疗策略。虽然含BNP的NP疗法已被批准用于人类急性充血性心力衰竭，但当务之急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，重要地将我们基于实验室的研究扩展到了解NPs的生理学和治疗潜力，以治疗人类疾病，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.