(Project 3) 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 newborn hypoxic neurological injuries. Project 3 will establish HIF pathway activation in term infants with hypoxic-ischemic encephalopathy (HIE) and cell-intrinsic HIF pathway functions during interneuron (IN) and oligodendrocyte (OL) ontogeny in developing animal systems.
The Specific Aims and hypotheses to be tested are: ? Aim1 is to determine activation of the HIF pathway in "Regions of Interest (ROIs)" defined in Projects 1, 2 and prior published work that include neural progenitors, oligodendroglia and late-migrating neurons in the term infant brain with HIE and controls. Hypothesis: HIE results in HIF pathway activation in human brain germinal zones and developing neuron and OL progenitors. ? Aim 2 is to determine functions of the HIF pathway in regulation of interneuron proliferation, migration and/or differentiation. Hypothesis: Interneuron cell-type specific conditional activation (using floxed VHL) or loss-of-function (using floxed HIF1?, HIF2?-null alleles) will result in abnormal precursor allocation, migration and/or differentiation. ? Aim 3 is to determine functions for HIF pathway in regulation of oligodendrocyte proliferation, migration and/or differentiation at pre- and post-natal stages. Hypothesis: Oligodendrocyte cell-type specific conditional activation (using floxed VHL) or loss-of-function (using floxed HIF1?, HIF2?-null alleles) will result in abnormal precursor allocation, migration and/or differentiation. Further, we will use explant approaches in transgenic mice and the ferret brain to answer these questions and determine conserved mechanisms of development and the injury response.
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