MATURATION OF DIAPHRAGM NEUROMUSCULAR TRANSMISSION

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The purpose of this research project is to study the role of neuromuscular transmission failure in the diaphragm and determine how this role changes with maturation. In addition, I will determine how neuromuscular transmission is modulated by chronic loading. My hypothesis is that neuromuscular transmission failure plays a significant role in the development of diaphragmatic fatigue in adults, and even more so in newborns. My specific aims are to: 1) determine whether neuromuscular transmission failure occurs in-vivo in chronically instrumented awake adult sheep during acute inspiratory flow resistive loaded breathing; 2) study the maturational changes in neuromuscular transmission during acute inspiratory flow resistive loaded breathing in awake lambs (ages <1 wk, 2 wk, 4 wk and 8 wk) ; 3) determine whether chronic inspiratory flow resistive loading improves neuromuscular transmission in the diaphragm in adult and newborn sheep, Measurements of indices of diaphragmatic function and neuromuscular transmission in-vivo (Pdi, EMG, single unit action potentials, phrenic neurogram, ventilation, blood gases) will be done using state-of-the-art techniques. Since this proposal presents an integrated approach to the study of neuromuscular transmission failure ad a function of age, it is highly likely to generate new information which will have direct relevance to our understanding of respiratory muscle function and failure in early life.