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

项目总结 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和 围产期血流减少，最终导致缺氧缺血性脑病(HIE) 在新生儿时期。围产期缺氧缺血性脑病的发病率为每1000名新生儿中有1-8例，并与 短期的内科并发症和长期的神经紊乱。婴幼儿心绞痛的治疗 新生儿缺氧缺血性脑病在新生儿管理方面仍然是一项艰巨的任务，尽管体温过低是最困难的 新生儿缺氧缺血性脑病的临床护理标准已被证明在以下方面取得了一定程度的成功 新生儿护理。因此，迫切需要发现对细胞和分子的新见解。 探讨围产期缺氧缺血性脑病的病理生理机制，并开发新的有效干预措施。我们 证明C型利钠肽(CNP)缺乏增加了新生儿的易感性 脑对小鼠缺氧缺血性脑病的影响，我们的初步数据显示，HI可下调小鼠脑内CNP水平 小老鼠。这些发现揭示了CNP在新生儿HIE发病中的一种新的先天神经保护作用。 老鼠模型。然而，CNP在新生儿中发挥先天神经保护作用的机制 大脑仍然未知。CNP的作用是通过CNP同源受体NPR2和NPR3介导的。 分别在神经元和脑血管内皮细胞中呈现细胞特异性表达。基于这些 结果，我们建议进行以下研究，以探讨CNP介导的分子机制 使用体外和体内模型，通过依赖NPR2和/或NPR3的途径发挥保护作用。 此外，我们验证了鼻腔给药CNP提供保护作用和 协同低温治疗对围产期小鼠缺氧缺血性脑病的影响。建议的研究已完成 在强大的科学前提下，将以创新和机械的方式探索新的概念。 这项应用的目的是确定CNP介导的保护的影响和潜在机制 围产期对小鼠缺氧缺血性脑病的影响及其治疗方法的探讨 CNP治疗围产儿缺氧缺血性脑病的潜力。拟议研究的结果不仅将推动我们的 了解新生儿缺氧缺血性脑病的病理生理机制，促进以CNP为基础的新疗法的发展 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.