Brain Pericytes in Perinatal Hypoxic-Ischemic Encephalopathy - PROJECT SUMMARY Perinatal hypoxic-ischemic encephalopathy (HIE) is caused by asphyxia, a lack of blood flow or gas exchange to or from the fetus in the period before, during, or after birth. It is a leading cause of acute mortality and chronic disability in newborns and is associated with short-term medical complications and long-term neurological disorders. The primary and secondary phases of HIE are characterized by episodes of energy and cell metabolism failures, accompanied by a series of neurotoxic events including oxidative stress, mitochondrial dysfunction, excitotoxicity, etc., consequently leading to neural cell death. It has been documented that up to 86% of term newborns who suffer from severe perinatal asphyxia develop cerebral edema, which is correlated to poor neurological outcomes. This underscores that cerebral vasculature is a promising therapeutic target for HIE. Pericyte coverage is required to maintain BBB integrity. Pericyte dysfunction is a major causative event in many disease episodes and is responsible for both gray and white matter damage. Therefore, targeting pericytes has been considered as a potential therapeutic strategy against cerebral vascular diseases in adulthood including dementia and ischemic stroke. The cerebral vascular maturation process happened in the postnatal period, including capillary expansion, pericyte recruitment, astrocytic endfoot coverage, etc. However, our knowledge of postnatal brain pericytes in this process is very limited, including physiology, specialization and transcriptomes, rendering the incomplete understanding of postnatal pericyte vulnerability and contributions to HIE. Many mechanisms have been associated with pericyte loss/death, such as activation of cell death pathway, and dysfunction of mitochondrial bioenergetics and metabolism. TANK-binding kinase 1 (TBK1) signaling pathway acts as a key regulator of pericyte survival to hypoxic-ischemic (HI) insult. TBK1 is the central kinase in nucleic acid immune sensing. Evidence showed that TBK1 regulates mitochondrial dynamics and bioenergetic conditions, and determines the cell fate. It also regulates the expressions of type I interferons and various cytokines, chemokines, MMPs, etc. by phosphorylation of IRF3 transcription factor and activation of NF-kB signal. These mechanisms may address the pericyte loss/death, and associated BBB damage under perinatal HIE. Based on this evidence, we will delineate brain pericyte specialization and association with BBB maturation using double reporter mice. We will determine the mechanism underlying the vulnerability of postnatal brain pericytes to HI. Finally, we will identify brain pericytes are therapeutic target by inhibition or conditional knockout of TBK1 signaling pathway after perinatal HIE.
