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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL053700-03
Application #
2771397
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1996-09-30
Project End
2000-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Tankersley, Clarke G; Broman, Karl W (2004) Interactions in hypoxic and hypercapnic breathing are genetically linked to mouse chromosomes 1 and 5. J Appl Physiol 97:77-84
Schneider, H; Patil, S P; Canisius, S et al. (2003) Hypercapnic duty cycle is an intermediate physiological phenotype linked to mouse chromosome 5. J Appl Physiol 95:11-9
Tankersley, Clarke G; Irizarry, Rafael; Flanders, Susan et al. (2002) Circadian rhythm variation in activity, body temperature, and heart rate between C3H/HeJ and C57BL/6J inbred strains. J Appl Physiol 92:870-7
Tankersley, Clarke G; Haxhiu, Musa A; Gauda, Estelle B (2002) Differential CO(2)-induced c-fos gene expression in the nucleus tractus solitarii of inbred mouse strains. J Appl Physiol 92:1277-84
Polotsky, V Y; Wilson, J A; Haines, A S et al. (2001) The impact of insulin-dependent diabetes on ventilatory control in the mouse. Am J Respir Crit Care Med 163:624-32
Tankersley, C G (2001) Selected contribution: variation in acute hypoxic ventilatory response is linked to mouse chromosome 9. J Appl Physiol 90:1615-22; discussion 1606
Tankersley, C G (2000) A genomic model for differential hypoxic ventilatory responses. Adv Exp Med Biol 475:75-85
Tankersley, C G; Elston, R C; Schnell, A H (2000) Genetic determinants of acute hypoxic ventilation: patterns of inheritance in mice. J Appl Physiol 88:2310-8
Tankersley, C G; Rabold, R; Mitzner, W (1999) Differential lung mechanics are genetically determined in inbred murine strains. J Appl Physiol 86:1764-9
O'donnell, C P; Schaub, C D; Haines, A S et al. (1999) Leptin prevents respiratory depression in obesity. Am J Respir Crit Care Med 159:1477-84

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