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.