A genomic approach to recurrent central apneas might provide pathogenic insight relevant to primary sleep apnea syndromes and neurological conditions associated with recurrent apneas and unstable breathing. The hypothesis is that naturally occurring genetic variations on mouse chromosome 1 underlie a phenotype of recurrent apneas following reoxygenation from hypoxia.
Aim 1 is to collect phenotype data on periodic breathing and DNA from~350 animals from 3-generational pedigrees derived from pairs of B6 x B6a1 intercross mice. This cross has been selected because 1 grandparent strain (b6a1) has lost the periodic breathing (PB) phenotype through substitution of A/J chromosome 1 onto the B6 genome.
Aim 2 will be to conduct a low resolution linkage scan using the first 100 F2 offspring from the B6 x B6a1 mating scheme to identify a smaller region(s) of mouse chromosome 1 that co-segregates with the periodic breathing phenotype.
Aim 3 is to perform a high resolution linkage scan on the region(s) identified in Specific Aim 2 using all remaining animals from the B6 x B6a1 mating scheme to fine map the location of the gene(s) responsible for the periodic breathing. This phase will utilize SNP markers at an approximate resolution of 20 SNPs/cM across the region(s) of interest.
In Aim 4, genotypes and phenotypes from recombinant inbred strains (Rl) derived from the B6 and A/J mouse strains will be compared to the mapping results to confirm the region(s) identified in Specific Aims 2 and 3 as modulators for periodic breathing, and strain-specific haplotype information for chromosome 1 will be used to predict which other mouse strains are likely to have periodic breathing. Identification of genetic regions that contribute significantly to the variance in ventilatory control in the mouse will give insight into functional networks informative to the current poor state of pharmacology for human sleep apnea, and for the risks of breathing instability observed in other medical and neurological conditions. ? ? ?
| Gillombardo, Carl B; Darrah, Rebecca; Dick, Thomas E et al. (2017) C57BL/6J mouse apolipoprotein A2 gene is deterministic for apnea. Respir Physiol Neurobiol 235:88-94 |
| Fechtner, Linnea; El Ali, Mazen; Sattar, Abdus et al. (2015) Fentanyl effects on breath generation in C57BL/6J and A/J mouse strains. Respir Physiol Neurobiol 215:20-9 |
| Feng, Pingfu; Hu, Yufen; Vurbic, Drina et al. (2014) Chromosome 1 replacement increases brain orexins and antidepressive measures without increasing locomotor activity. J Psychiatr Res 59:140-7 |
| Moore, Michael W; Akladious, Afaf; Hu, Yufen et al. (2014) Effects of orexin 2 receptor activation on apnea in the C57BL/6J mouse. Respir Physiol Neurobiol 200:118-25 |
| Gillombardo, C Barton; Yamauchi, Motoo; Adams, Mark D et al. (2012) Identification of novel mouse genes conferring posthypoxic pauses. J Appl Physiol 113:167-74 |
| Hager, Stefanie; Lösch, Saskia; Noll, Stephan et al. (2012) Red/ET recombination with chimeric oligonucleotides allows rapid generation of BAC transgenes harboring full-length or truncated huntingtin cDNA. Biotechniques 53: |
| Chai, Sam; Gillombardo, Carl B; Donovan, Lucas et al. (2011) Morphological differences of the carotid body among C57/BL6 (B6), A/J, and CSS B6A1 mouse strains. Respir Physiol Neurobiol 177:265-72 |
| Donovan, Lucas M; Chai, Sam; Gillombardo, Carl B et al. (2011) Ventilatory behavior and carotid body morphology of Brown Norway and Sprague Dawley rats. Respir Physiol Neurobiol 178:250-5 |
| Yamauchi, Motoo; Kimura, Hiroshi; Strohl, Kingman P (2010) Mouse models of apnea: strain differences in apnea expression and its pharmacologic and genetic modification. Adv Exp Med Biol 669:303-7 |
