The protective effects of c-type natriuretic peptide in the neonatal brain

项目摘要 围产期缺氧缺血（HI）是一种严重的围产期事件，其特征是暴露于低氧环境， 围产期血流减少，最终导致缺氧缺血性脑病（HIE） 在新生儿围产期HIE的发生率为1-8例/1000例新生儿， 短期的医疗并发症和长期的神经系统疾病。治疗患有 HIE仍然是一个困难的任务，在新生儿管理，虽然体温过低，这是一个很好的治疗方法。 标准的临床护理新生儿缺氧缺血性脑病，已被证明提供一定程度的成功， 新生儿护理因此，迫切需要揭示细胞和分子生物学的新见解， 围产期缺氧缺血性脑病的病理生理学机制，并开发新的有效干预措施。我们 表明C型利钠肽（CNP）缺乏增加了新生儿的脆弱性， 我们的初步数据表明，HI损伤下调了脑CNP水平， 小老鼠这些发现揭示了CNP在新生儿HIE中的一种新的先天性神经保护作用 小鼠模型然而，CNP在新生儿中的先天性神经保护作用的潜在机制 大脑仍然未知。CNP的作用由CNP同源受体NPR 2和NPR 3介导， 分别在神经元和脑血管内皮细胞中表现出细胞特异性表达。基于这些 研究结果，我们提出了以下研究，以探讨CNP介导的分子机制， 使用体外和体内模型通过NPR 2和/或NPR 3依赖性途径的保护作用。 此外，我们检验了CNP鼻内给药提供保护作用的假设， 协同低温治疗对小鼠幼仔围产期HIE的影响。该研究旨在建立 在强大的科学前提下，并将探索一个新的概念与创新和机械的方法。 本申请的目的是确定CNP介导的保护性细胞因子的影响和潜在机制。 在小鼠仔鼠围产期缺氧缺血性脑病中的作用，至关重要的是，探索治疗 CNP治疗围产期HIE的潜力。建议的研究结果不仅将促进我们的 了解新生儿缺氧缺血性脑病的病理生理，但促进新的CNP为基础的发展 围产期新生儿缺氧缺血性脑病的治疗策略

PROJECT SUMMARY Perinatal hypoxic-ischemia (HI) is a critical perinatal event that is characterized by exposure to low oxygen and decreased blood flow during the perinatal period, ultimately leading to hypoxic-ischemic encephalopathy (HIE) in newborn. Perinatal HIE happens with an incidence of 1-8 cases per 1000 newborns, and is associated with the short-term medical complications and the long-term neurological disorders. The treatment of infants with HIE remains a difficult task for neonatologists in neonatal management, albeit hypothermia, which is the standard of clinical care for newborns with HIE, has been proven to provide some degree of success in neonatal care. Thus, there is an urgent need to uncover new insights into the cellular and molecular mechanisms underlying the pathophysiology of perinatal HIE, and to develop new effective interventions. We demonstrated that the c-type natriuretic peptide (CNP) deficiency increased the vulnerability of the neonatal brains to HIE in mouse pups, and our preliminary data showed that HI insult downregulated brain CNP levels in mouse pups. These findings revealed a novel innate neuroprotectant role of CNP in the setting of neonatal HIE mouse model. However, the mechanisms underlying the innate neuroprotectant role of CNP in the neonatal brain remain unknown. The action of CNP is mediated by CNP cognate receptors NPR2 and NPR3, which exhibit cell-specific expression in neurons and cerebrovascular endothelial cells, respectively. Based these findings, we propose the following studies to investigate the molecular mechanisms of CNP-mediated protective effects through NPR2- and/or NPR3-dependent pathways using in vitro and in vivo models. Furthermore, we test the hypothesis that intranasal administration of CNP provides protective effects and synergizes the effects of hypothermia treatment on perinatal HIE in mouse pups. The proposed study is built upon strong scientific premise, and will explore a novel concept with an innovative and mechanistic approach. The goal of this application is to determine the impact and underlying mechanisms of CNP-mediated protective effects in the setting of perinatal HIE in mouse pups, and of critical importance, to explore the therapeutic potential of CNP treatment for perinatal HIE. The outcome of the proposed study will not only advance our understanding of the pathophysiology of neonatal HIE, but promote the development of new CNP-based therapeutic strategies for perinatal HIE treatment in newborn.