Background. Increased morbidity and mortality have been shown in individuals predisposed to retaining hypercapnic hypoventilation. This association is especially relevant coincident with other respiratory disease states including obesity-hypoventilation, sudden infant death syndrome, chronic obstructive pulmonary disease, and asthma. This resubmission demonstrates and proposes to investigate the genetic control of ventilation addressing the supposition that individuals susceptible to hypoventilatory syndromes may be at greater mortality risk given certain pulmonary disease processes. Unique animal models have been developed which take advantage of phenotypic differences between highly inbred murine strains to examine the genetic determinants that govern ventilatory mechanisms. Overall Objective. The primary objective of this proposal is to identify major and modifying genes that influence baseline breathing pattern and hypercapnic ventilation in inbred mice strains. Preliminary data suggest that a definitive number of genes exist which regulate baseline breathing and hypercapnic ventilatory responses between C57BL/6J and C3H/HeJ strains of mice. Strain differences will be investigated to determine the physiological and biochemical mechanisms which underlie phenotypic variation in these traits. Ventilatory responses of segregant progeny and recombinant inbred (RI) strains will be evaluated. Selective genotyping and linkage analysis will be performed to enumerate and position genes determining strain differences in normal and hypercapnic breathing. Specific Hypotheses.
In Specific Aim 1, ventilatory phenotypes are characterized more precisely by exploring strain differences with respect to body temperature, oxygen consumption, and arterial blood gas and pH.
In Specific Aims 2 and 3, we will test the hypotheses that baseline breathing frequency and hypercapnic ventilatory sensitivity are traits controlled by as few as two gene loci. BXH RI strains will be examined to initiate chromosomal map assignments. Selective genotyping and linkage analyses will be used to confirm the number and relative position of major and modifying genes which influence normal and hypercapnic breathing.
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