PROJECT SUMMARY ABSTRACT
Long-term cognitive impairment and learning disabilities are a major public health concern that affects more
than half of infants born very preterm with immature lung injury. Such infants have a global delay in cerebral
maturation of gray and white matter structures, likely caused by high susceptibility to hypoxia-induced oxidative
stress during this critical period. This stress can result in mitochondrial dysfunction. If mitochondrial-dependent
oxidative metabolism is required for immature progenitor cells to mature, then mitochondrial dysfunction can
result in failure of timely progenitor cell maturation. Little is known about the metabolic alterations or the
dependence of neural progenitor cell maturation on mitochondrial metabolism in the developing brain. Our
work will fill this gap in knowledge. We use a rodent model of chronic hypoxia to recapitulate the immature lung
injury commonly found in very preterm infants, which causes global gray and white matter cellular dysmaturity
and associated ultrastructural and behavioral deficits. In this study, we will investigate the metabolic effects of
hypoxia on hippocampal dysmaturation and determine the developmental outcome of mitochondrial disruption.
Our preliminary data on the hippocampus indicate that: i) hypoxia causes long-term decreases in biochemical
markers of mitochondrial function; ii) hypoxia impairs expression of pyruvate dehydrogenase E1a independent
of its inhibitors; and iii) conditional removal of pyruvate dehydrogenase E1a from GFAP-expressing radial glia
stem cells prevents their maturation. A potential target for promoting recovery after perinatal brain injury is
timely restoration of mitochondrial function and oxidative metabolism. Our published and preliminary data
strongly suggest the novel findings that intranasal heparin-binding epidermal growth factor [HB-EGF] treatment
after hypoxia may reverse hypoxia-induced cellular dysmaturation, restore mitochondrially produced N-acetyl
aspartate, and ameliorate neurobehavioral deficits by targeting the mitochondria. We hypothesize that
mitochondrial dysfunction results in delayed development of hippocampal neural progenitor cell capacity to
perform oxidative energy metabolism, thus preventing their maturation. We will test the hypothesis that
restoring mitochondrial function will enable these cells to meet their bioenergetic demands, permitting timely
cellular maturation and recovery of function in the hippocampus. These hypotheses will be tested in three
specific aims. In Aim 1, we will determine whether hypoxia impairs mitochondrial function in the hippocampus.
In Aim 2, we will determine whether hypoxia or cell-specific removal of pyruvate dehydrogenase E1a in
hippocampal neural progenitor cells delays differentiation and hippocampal behavioral deficits. In Aim 3, we
will determine whether intranasal HB-EGF treatment after hypoxia enhances mitochondrial function.
Successful completion of these aims will elucidate a fundamental biochemical mechanism that determines
differentiation failure of neural progenitor cells after hypoxia-induced injury and define a novel metabolic
mechanism by which HB-EGF facilitates cellular and functional recovery after neonatal brain injury.