Abstract

 

Grant Number:          P30 DK072482-01

 

Core B PI Name:       BEDWELL, DAVID M.

 

PI Email:                     dbedwell@uab.edu

 

PI Title:                       PROFESSOR

 

Core B Title:              Mouse Models Core

 

Core B will breed and genotype CF mouse models including Cftrtm1UNC and congenic derivatives thereof, Cftrtm1CAM, CftrG551D, CftrR117H , as well as FABP-human CFTR+/- transgenic (Tg) mice in a Cftr -/- background. The Core will also propagate a p11 knock-out mouse intended for studies of CFTR membrane recycling, and help P30 investigators test the influence of defective TGF-β signaling on the CF phenotype using a TGF receptor-defective mouse characterized at our institution.  New CF mice will be generated in the Core, including knock in mouse models encoding prematurely truncated CFTR (Class I mutations).  In addition, Tg(Scgb1a1-Scnn1b)  (a murine model exhibiting a CF-like pulmonary phenotype) will be provided to P30 investigators for projects such as those to investigate new mediators of inflammation in CF lung disease.

 

Core B will also conduct testing with novel flexiVent equipment for assessing murine lung function. This system measures resistance, elastance and compliance (and performs pressure-volume loop measurements of murine lungs), and can aerosolize compounds while simultaneously recording lung function in real-time.  Like other laboratories, we have found that this sensitive equipment can discriminate CF from non-CF mice. The capabilities will allow us to evaluate new inflammatory pathways (HMGB1 and PGP) in CF airways.  Preclinical assessment of CF therapies (PTC124) can be accomplished in the same way. Core B is experienced with bioelectric methods necessary to track changes in CFTR activity in vivo or ex vivo (transepithelial potential difference; short circuit current) and will provide these to P30 investigators who require the measurements for their CF research programs.

 

In summary, Core B will provide mouse models and conduct state-of-the art assays necessary to examine CF disease mechanism in vivo, and facilitate preclinical evaluation of experimental therapeutics for the disease.