Boehning, Darren F2016-11-142016-11-142012-12December 2http://hdl.handle.net/2152.3/840Neonatal hypoxia-ischemia (HI) affects 60% of low birth weight infants and up to 40% of preterm births. Due to the increasing incidence of preterm and low birth weight infants and the lack of adequate treatment for HI, characterization of brain injury after HI remains an extremely relevant area of interest. Severe HI causes immediate necrosis of neuronal cells, and secondary apoptosis of surrounding cells due to neuronal inflammation. Hence, we sought to characterize the biochemical pathways associated with cell death after HI, as well as the extent of neurological injury that is transferred to the next generation. Bax, a cell death signaling protein, is activated after HI, and translocates to the nucleus, ER, and mitochondria. Translocation patterns of Bax affect the cell death phenotype (necrotic or apoptotic) observed. Once activated, Bax is known to oligomerize. However, little is understood about the factors that control translocation and oligomerization of Bax. We hypothesized that phosphorylation and interaction with kinases determines Bax intracellular localization and oligomerization. Using well-established in vivo and in vitro models of neonatal HI, we characterized Bax oligomerization and multi-organelle translocation. We found that HI-dependent phosphorylation of Bax determines its oligomerization status and multi-organelle localization, and ultimately the cell death phenotype observed. Cell death and brain injury after HI have been shown to cause long-lasting behavioral deficits. Neurological injuries have previously been shown to cause epigenetic changes, affecting generations to come. By using a battery of behavioral tests on second generation 3-week-old rodents, we found that neonatal HI is associated with behavioral consequences in progeny. Our results suggest an epigenetic transfer mechanism of the neurological symptoms associated with neonatal HI. Elucidating the transfer of brain injury to the next generation after HI calls attention to the risks associated with HI injury and the need for proper treatment to reverse these effects. Understanding the mechanisms of Bax translocation will aid in the rational design of specified therapeutic strategies which could potentially involve altering Bax subcellular redistribution to decrease the irreversible trauma resulting from a prolonged inflammatory response.application/pdfhypoxia-ischemia, Bax, cell death, cortex, epigenetics, behaviorThesis2016-11-14