Projects per year
The cystic fibrosis transmembrane conductance regulator (CFTR) is a novel member of the ATP-binding cassette (ABC) transporter superfamily that forms an anion channel with complex regulation. CFTR is predominantly located in epithelia lining ducts and tubes throughout the body, although it is also expressed in some non-epithelial tissues, most notably cardiac myocytes. In epithelia, CFTR provides a pathway for the movement of chloride (Cl-) and bicarbonate anions across the apical (lumen-facing) membrane and a key point at which to regulate the rate of transepithelial salt and water transport.
Dysfunction of the CFTR Cl- channel is associated with a wide spectrum of disease. Mutations that, in general, abolish the function of CFTR cause the genetic disease cystic fibrosis (CF), which affects multiple organ systems in the body. By contrast, some forms of male infertility, chronic pancreatitis and bronchiectasis are caused by mutations that probably preserve partial CFTR function. These conditions, termed CFTR-related diseases, affect a single organ system in the body. Increased or inappropriate activity of the CFTR Cl- channel is associated with other diseases, such as secretory diarrhoea and autosomal dominant polycystic kidney disease.
In our studies of the CFTR, we have three specific research goals:
To understand the relationship between the structure and function of the CFTR Cl- channel
To learn how CF-associated mutations cause a loss of CFTR function
To identify new modulators of CFTR that might prove to be of value in the treatment of disease and elucidate their mechanism of action.
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31/10/08 → 31/10/11
THE USE OF HUMAN-MURINE CFTR CHIMERAS TO INVESTIGATE THE COUPLING OF PERMEATION AND GATING IN THE CFTR CHLORIDE CHANNEL
1/05/05 → 1/05/08
Can two wrongs make a right? F508del-CFTR ion channel rescue by second-site mutations in its transmembrane domainsPrins, S., Corradi, V., Sheppard, D. N., Tieleman, D. P. & Vergani, P., 1 Mar 2022, In: Journal of Biological Chemistry. 298, 3, p. 1-14 14 p., 101615.
Research output: Contribution to journal › Article (Academic Journal) › peer-reviewOpen AccessFile6 Downloads (Pure)
CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftorRaraigh, K. S., Paul, K. C., Goralski, J. L., Worthington, E. N., Faino, A. V. & Sheppard, D. N., 22 Mar 2022, In: JCI Insight. 7, 6, p. 1-15 e148841.
Research output: Contribution to journal › Article (Academic Journal) › peer-reviewOpen AccessFile3 Downloads (Pure)
Scholl, D., Wang, Y., Sheppard, D. N., Govaerts, C. & al., E., Sep 2021, In: Nature Chemical Biology. 17, 9, p. 989-997 9 p.
Research output: Contribution to journal › Article (Academic Journal) › peer-reviewOpen AccessFile14 Downloads (Pure)
Differential thermostability and response to cystic fibrosis transmembrane conductance regulator (CFTR) potentiators of human and mouse F508del-CFTR [UPDATED version available]
Sheppard, D. N. (Creator), Wang, Y. (Creator), Cai, Z. (Contributor), Bijvelds, M. J. (Contributor), Bot, A. G. M. (Contributor) & Jonge, H. R. D. (Contributor), University of Bristol, 25 Jan 2019
Differential thermostability and response to cystic fibrosis transmembrane conductance regulator (CFTR) potentiators of human and mouse F508del-CFTR
Sheppard, D. N. (Creator), Wang, Y. (Creator), Cai, Z. (Contributor), Bijvelds, M. J. C. (Contributor), Bot, A. G. M. (Contributor) & Jonge, H. R. D. (Contributor), University of Bristol, 16 Apr 2019
Correlating genotype with phenotype using CFTR-mediated whole-cell Cl- currents in human nasal epithelial cells