Grant: Project Grant

Neonatal hypoxic-ischemic brain injury (HIBI) manifests as hypoxic-ischemic encephalopathy in neonates and is a major cause of neonatal death and chronic neurological disabilities globally. Therapeutic hypothermia (body cooling) is the current standard of care for hypoxia-ischemia (HI)-related brain injury. However, many moderately to severely affected infants continue to have poor outcomes despite therapeutic hypothermia treatment. This highlights the urgent need for novel intervention to enhance neuroprotection. The ryanodine receptor 2 (RyR2), a calcium release channel highly expressed in the brain, is a key player in mediating HI-induced cell death. Recently, we reported that a clinically used drug dantrolene, an RyR2 inhibitor, has profound neuroprotective effect in a neonatal HIBI mouse model. This finding suggests that RyR2 may be a promising target for treating neonatal HIBI. To test this idea, we have recently conducted pilot experiments and found that neonatal HIBI was substantially reduced in genetically modified mice with suppressed RyR2 function, supporting the notion that RyR2 is critical for the origination and development of neonatal HIBI. In this project, we propose to define the role RyR2 in neonatal HIBI using genetically modified mice, understand the cellular mechanisms underlying RyR2-mediated HIBI using state-of-the-art electrical recording and calcium imaging techniques, and evaluate the therapeutic potential of novel RyR2 inhibitors. We have established a strong collaborative research team with multidisciplinary expertise in RyR2, neonatal HIBI animal model, drug development, and neonatal brain disease. We expect that our proposed preclinical studies will verify RyR2 as a promising therapeutic target for neonatal HIBI, and lead to the development of novel RyR2-targeted drugs for treating neonatal HI-induced brain injury.