The carotid body (CB), a major hypoxic chemosensory organ, induces reflex responses in many vital organs. The hypoxic responses among individuals are variable, and genetic differences may be an underlying mechanism. Examples can be seen in humans as well as inbred strains of mice. We have shown that a large CB and robust hypoxic responses in DBA/2J mice, and a small CB and weak responses in A/J mice. Our preliminary data show that these differences in the CBs develop after birth. Our other important findings are: (1) The expression of GDNF mRNA in the CB of DBA/2J mice was higher than in the CB of A/J mice. (2) GDNF gene expression correlated to glomus cell (GC) number index in the DBA/2J, A/J and offspring mice. (3) The number of GCs increased from 1-day to 4-week-old in DBA/2J mice, but not in A/J mice. (4) Proliferation of GCs was more robust in DBA/2J than in A/J mice at 1-2 weeks of age. (4) Expression and activity of BK channels in GCs were high in DBA/2J mice and low in A/J mice. (5) When CBs of young A/J mice were cultured with GDNF, BK channel mRNA and channel activity became similar to that of DBA/2J mice. (6) Hypoxic sensitivity, monitored by voltage-dependent K channel activity in GCs and intracellular Ca2+ in CBs, was higher in DBA/2J than in A/J mice. Based on these observations and literature search, we have hypothesized: (1) GDNF plays a critical role for postnatal survival and growth of GCs. (2) GDNF promotes the expression of BK channels, which support postnatal survival and hypoxic sensitivity of GCs.
Specific aims of this proposal are to determine: (1) the role of GDNF for postnatal survival and growth of GCs; (2) if GDNF promotes the expression of BK channels in developing GCs; (3) the role of BK channels for postnatal survival of GCs; (4) if the GDNF-mediated BK channel expression supports hypoxic sensitivity of GCs during postnatal development. A newly developed whole CB culture system together with patch clamp, Ca2+ imaging, RT-PCR (using whole CB and single GC), morphometry, and immunohistochemistry will be applied. Studying genetic bases of postnatal maturation of the CB may provide some insights into hypoxic chemoreception and chemotransduction pathways. Further, therapeutic measures may be developed for CB-related diseases such as sudden infant death syndrome, congenital hypoventilation syndrome, ventilatory problems in Prader-Willi syndrome, chronic heart failure, and primary hypertension. ? ? ?
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