(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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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University of California San Francisco
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