Mechanisms of Congenital Hypoventilation

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 DESCRIPTION (provided by applicant): Incomplete respiratory neuron maturation causes significant morbidity during the perinatal period, yet the mechanisms by which respiratory neuron maturation occurs during this vulnerable time window is not understood. Thus, there is a critical need to identify these basic neural mechanisms of perinatal respiratory control. The objectives of the proposed research are to elucidate developmental processes of respiratory neuron network maturation and to identify brainstem respiratory centers/circuits necessary for perinatal breathing. The central hypothesis is that hindbrain respiratory neuron networks undergo critical developmental maturation during the late embryonic, perinatal, and post-natal periods in mammals, and that developmental abnormalities in neuronal and glial maturation contribute to the pathophysiology of autonomic respiratory neuron dysfunction. The proposed research is inspired by our group's findings of Central Congenital Hypoventilation Syndrome (CCHS), a rare human disorder characterized by an inability to sense CO2 and which is linked to PHOX2B poly-alanine repeat and non-polyalanine repeat (NPARM) mutations. The rationale for the proposed research is that the lack of a basic fundamental understanding of which autonomic neural circuits are required for perinatal breathing represents a barrier to the ultimate implementation of interventions aimed at improving morbidity for premature infants. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine the extent to which selective expression of a dominant negative NPARM-PHOX2B mutation regulates perinatal chemosensation-induced respiratory drive, 2) Determine which brainstem circuits are lost in NPARM-CCHS, and 3) Determine the extent to which selected ablation of brainstem astrocyte population promote congenital hypoventilation. Under the first aim, we will test the effects on ventilation control and brainstem anatomy after targeted brainstem expression of a dominant negative NPARM PHOX2B mutation using an already proven conditional transgenic mouse approach. In the second aim, we will combine an innovative transgenic approach to identify which brainstem circuits are lost in congenital hypoventilation. In the third aim, we will determine the extent to which neuronal-glial interaction are necessary for appropriate autonomic respiratory control in the perinatal and post-natal period. The approach is innovative because it uses novel and validated tools, techniques, and reagents from distinct disciplines that allow us to address previously unanswerable questions. The proposed research is significant, because it is expected to vertically advance and expand understanding of which neuronal-glial circuits are required for proper control of autonomic regulation of breathing at birth. The tools and basic knowledge gained from these studies will form the foundation of future studies where interventions to improve autonomic respiratory neuron function in premature babies are designed and validated.