Man and mouse are currently the only two species that display cystic tibrosis and both can demonstrate significant variation between affected individuals. It seems clear that at least some of the variation is genetic in nature, prompting the use of genetic strategies and state of the art molecular technology to find the genes involved. The restriction of CF to mouse and man limits the choice of model systems one can use to identify genes that modify cystic fibrosis. Of the two, human is obviously the more relevant model to study, but there are significant limitations to carrying out genetic studies in humans. Therefore, the mouse can be used as an adjunct to human studies, providing the ability to control both genetic and non-genetic factors not possible with humans. The drawback, however,.is that one may potentially sacrifice relevance, as there may be CF-associated characteristics between the two species that pertain little to each other. If a model system, such as the mouse, is used to identify genes relevant to CF, it would have the highest chance of success if the phenotypes studied are also relevant to CF, whether it be at the clinical, cellular or biochemical level. In this application we propose to exploit the benefits of the mouse systems by identifying loci that modify CF or CF-related phenotypes. In a related application, we will determine if the human homologues of those genes influence CF in humans. To achieve the goals of this application, the first specific aim is to map loci causing variation in mice for traits relevant to CF, such as those involved responses to Pseudomonas aeruginosa, and CFdependent growth retardation. Our preliminary findings on ion transport genetics indicate multiple genes are involved in the observed variation. For those traits showing multiple contributing loci, we wish to know the contribution of individual loci and how they interact with each other. Therefore, the second aim is to generate congenic mice for loci identified in Aim 1 and related projects by backcrossing and intercrossing consomic mice. Congenics will be generated on both on CF and non-CF backgrounds. Altering CFTR levels appears to have a significant phenotypic effect in patients, but regulatory mechanisms of CFTR expression are poorly understood. We have found tissue- and strain dependent differences in Cftr expression, allowing the potential identification of Cftr transcriptional regulators. Toward this end, the third aim is to identify transcriptional control elements of the Cftr promoter and corresponding transcription factors. The overall goal is to identify genes that affect, or can be manipulated to affect, disease severity in CF patients. To reach that goal, the genes in question must be isolated and their human counterparts identified for study. For this, the final aim is:to identify genes controlling phenotypes in Aim I and controlling expression in Aim 3, as well as their human homologues.
|Bartling, Toni R; Drumm, Mitchell L (2009) Loss of CFTR results in reduction of histone deacetylase 2 in airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 297:L35-43|
|Bartling, Toni R; Drumm, Mitchell L (2009) Oxidative stress causes IL8 promoter hyperacetylation in cystic fibrosis airway cell models. Am J Respir Cell Mol Biol 40:58-65|
|Hodges, Craig A; Palmert, Mark R; Drumm, Mitchell L (2008) Infertility in females with cystic fibrosis is multifactorial: evidence from mouse models. Endocrinology 149:2790-7|
|Rosenberg, Lewis A; Schluchter, Mark D; Parlow, Albert F et al. (2006) Mouse as a model of growth retardation in cystic fibrosis. Pediatr Res 59:191-5|
|Grubb, Barbara R; Gabriel, Sherif E; Mengos, April et al. (2006) SERCA pump inhibitors do not correct biosynthetic arrest of deltaF508 CFTR in cystic fibrosis. Am J Respir Cell Mol Biol 34:355-63|
|Jin, R; Hodges, C A; Drumm, M L et al. (2006) The cystic fibrosis transmembrane conductance regulator (Cftr) modulates the timing of puberty in mice. J Med Genet 43:e29|
|Ulatowski, Lynn M; Whitmore, Kirstin L; Romigh, Todd et al. (2004) Strain-specific variants of the mouse Cftr promoter region reveal transcriptional regulatory elements. Hum Mol Genet 13:1933-41|