Human brain complexity is considered unique, yet the genesis of many neuronal and glial sub-types and their migration and integration into functional circuits in neonates remains poorly understood. Moreover, these processes are likely disrupted in hypoxic neurological injuries, which can result in death, cerebral palsy and/or long-term cognitive disabilities. The proposed program focuses on human interneuron (IN) and oligodendrocyte precursor (OPC) development during 3rd trimester (24-40 weeks) gestation, and whether lineage ontogeny, migration and differentiation is regulated by oxygen levels and the hypoxia-inducible factor (HIF) pathway. This program is an outgrowth of the investigators common interests, productive collaborations and the close association of their laboratories in the recently built Ray and Dagmar Dolby Building in the Eli and Edythe Broad Institute for Regeneration Medicine and Stem Cell Research at UCSF. The investigators have studied the human fetal and newborn brain and recently identified (1) the outer subventricular zone (OSVZ), (2) chain migration of young neurons of medial migratory stream (MMS) and (3) the impact of injury on oligodendrocyte development in infants with hypoxic-ischemic encephalopathy (HIE). We propose three projects and cores to promote an understanding of human brain development and injury. Project 1 investigates migration of young INs to focal regions of human newborn brain, their differentiation and the developmental impact of oxygen- regulated pathways. Project 2 will define structure and OPC production of the human OSVZ from 24-40 weeks gestation, and regulation of lineage ontogeny by oxygen levels. Project 3 will provide direct evidence for HIF pathway activation in IN and OPC populations in human neonates with HIE, and cell-intrinsic functions of HIF pathway genes during pre- and post-natal IN and OPC development. The administrative core (A) provides budgetary oversight, coordination and access to resources. All projects will use primary human neuropathological specimens for histological analysis supported by a neuropathology core (B). All projects will employ animal experimental systems. Based on compelling preliminary data, we propose an animal model core (C) to support studies in neonatal ferret brain.
The proposed research is intended to provide new insight into a critical window of brain development in the 3rd trimester of human pregnancy, when preterm and term infants are especially vulnerable to brain injuries leading to cerebral palsy and lifelong neuro-cognitive disabilities.
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