Abstract □ 96

Early physiological studies have suggested that familial or genetic factors are especially important determinants of ventilatory drives and may have important influences on ventilation in patients with respiratory disease. Epidemiological studies have shown that sleep-related-breathing disorders aggregate in the same families. Establishment of techniques that modify the genome provides ways to reproduce genetic alterations in the mouse. Developed gene knockout techniques allow to generate null-mutant mice. Experiments in knockout mice indicate that central neural network controlling rhythm generation in embryonic hindbrain are specified during early development of the rhombencephalon. Inactivation of genes such as Krox-20 compromises neonatal survival and affects respiration after birth. Neurotrophic factors such as brain-derived-neurotropic-factor (BDNF) are required for the development of the central respiratory rhythm in mice. BDNF knockout newborn mice exhibit severe respiratory abnormalities with reduced peripheral chemosensory drive. Genes implicated in the development of vagal and/or cephalic neural crest cells may be involved in the development of chemosensibility. The ret knockout mice have a depressed ventilatory response to hypercapnia. Impaired ventilatory responses to hypoxia and hypercapnia have been reported in mutant deficient mice in endothelin-1. The transcription factor Mash-1 controls the differentiation of noradrenergic pathways in the central nervous system. Heterozygous Mash-1 newborn mice have a decreased ventilatory response to chemical stimuli. Therefore, combined genetic analysis and respiratory physiological measurements from knockout mice might lead to the emergence of understanding of the cascade of molecular signals that might be involved in the underlying mechanisms of early disturbances of respiratory control in human infants.

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