CF Research Consortia

On this page:

• CFTR Folding Consortium
• CFTR 3D Structure Consortium 
• Mucocilliary Clearance Consortium
• CF Biomarker Consortium 

CFTR Folding Consortium

The CFTR Folding Consortium is composed of a group of investigators dedicated to understanding the process of CFTR folding and trafficking and developing and distributing reagents (antibodies and protein) and methods to facilitate a practical understanding of:

1. why disease-associated CFTR mutants misfold; and
2. how to correct these defects.

Methods and reagents are made available to researchers focused on these two goals. Investigators who utilize these resources are required to provide feedback on their utility and are asked to make available any new, improved reagents or methods they developed from the resources. This work is funded by Cystic Fibrosis Foundation Therapeutics (CFFT).

Consortium Membership

Suggested Reading:

Du K, Lukacs GL. Cooperative assembly and misfolding of CFTR domains in vivo. Mol Biol Cell. 2009 Apr;20(7):1903-15. Epub 2009 Jan 28.PMID: 19176754

Kleizen B, van Vlijmen T, de Jonge HR, Braakman I. Folding of CFTR is predominantly cotranslational. Mol Cell. 2005 Oct 28;20(2):277-87.PMID: 16246729

Nakatsukasa K, Huyer G, Michaelis S, Brodsky JL. Dissecting the ER-associated degradation of a misfolded polytopic membrane protein. Cell. 2008 Jan 11;132(1):101-12.PMID: 18191224

Caohuy H, Jozwik C, Pollard HB. Rescue of DeltaF508-CFTR by the SGK1/Nedd4-2 signaling pathway. J Biol Chem. 2009 Sep 11;284(37):25241-53. Epub 2009 Jul 17.PMID: 19617352

Cebotaru L, Vij N, Ciobanu I, Wright J, Flotte T, Guggino WB. Cystic fibrosis transmembrane regulator missing the first four transmembrane segments increases wild type and DeltaF508 processing. J Biol Chem. 2008 Aug 8;283(32):21926-33. Epub 2008 May 28.PMID: 18508776

Peters KW, Okiyoneda T, Balch WE, Braakman I, Brodsky JL, Guggino WB, Penland CM, Pollard HB, Sorscher EJ, Skach WR, Thomas PJ, Lukacs GL, Frizzell RA. CFTR Folding Consortium: methods available for studies of CFTR folding and correction. Methods Mol Biol. 2011;742:335-53.PMID:21547742 [PubMed - in process]

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CFTR 3D Structure Consortium

Elucidating the three-dimensional structure of CFTR will enhance our understanding of the mechanism of CFTR function and thereby provide insight into the effects of mutations that lead to CF. This understanding will be critical to the ultimate goal of finding the means to cure and control CF by enabling structure-based drug discovery efforts.

The CFTR 3D Structure Consortium intends to accelerate efforts to obtain this structural information. The Consortium members work together to expand knowledge of the structure, energetics and mechanism of CFTR function.

The Consortium's goals are to:

• Obtain high quality protein reagents for full-length CFTR and CFTR structural domains;
• Characterize the physicochemical properties of CFTR and CFTR structural domains;
• Obtain high resolution 3D structures of interactions between structural domains of CFTR;
• Obtain high resolution 3D structures of the full length CFTR protein; and
• Obtain knowledge of the binding location and energetic/folding consequences of CFTR modulators on CFTR or CFTR domains.

Consortium Membership

Suggested Reading:

X-ray (and mass spec) Studies of CFTR

Lewis HA, Wang C, Zhao X, Hamuro Y, Conners K, Kearins MC, Lu F, Sauder JM, Molnar K, Coales SJ, Maloney PC, Guggino WB, Wetmore DR, Weber PC, Hunt JF. Structure and Dynamics of NBD1 from CFTR Characterized Using Crystallography and Hydrogen/Deuterium Exchange Mass Spectrometry. J Mol Biol. 2009 Nov 26. [Epub ahead of print]

Lewis HA, Zhao X, Wang C, Sauder JM, Rooney I, Noland BW, Lorimer D, Kearins MC, Conners K, Condon B, Maloney PC, Guggino WB, Hunt JF, Emtage S. Impact of the deltaF508 mutation in first nucleotide-binding domain of human cystic fibrosis transmembrane conductance regulator on domain folding and structure. J Biol Chem. 2005 Jan 14;280(2):1346-53.

Thibodeau PH, Brautigam CA, Machius M, Thomas PJ. Side chain and backbone contributions of Phe508 to CFTR folding. Nat Struct Mol Biol. 2005 Jan;12(1):10-6.

Lewis HA, Buchanan SG, Burley SK, Conners K, Dickey M, Dorwart M, Fowler R, Gao X, Guggino WB, Hendrickson WA, Hunt JF, Kearins MC, Lorimer D, Maloney PC, Post KW, Rajashankar KR, Rutter ME, Sauder JM, Shriver S, Thibodeau PH, Thomas PJ, Zhang M, Zhao X, Emtage S. Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator. EMBO J. 2004 Jan 28;23(2):282-93.

NMR Studies of CFTR

Kanelis V, Hudson RP, Thibodeau PH, Thomas PJ, Forman-Kay JD. NMR evidence for differential phosphorylation-dependent interactions in WT and DeltaF508 CFTR. EMBO J. 2009 Nov 19. [Epub ahead of print]

Baker JM, Hudson RP, Kanelis V, Choy WY, Thibodeau PH, Thomas PJ, Forman-Kay JD. CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices. Nat Struct Mol Biol. 2007 Aug;14(8):738-45.

EM Studies of CFTR

Zhang L, Aleksandrov LA, Zhao Z, Birtley JR, Riordan JR, Ford RC. Architecture of the cystic fibrosis transmembrane conductance regulator protein and structural changes associated with phosphorylation and nucleotide binding. J Struct Biol. 2009 Sep;167(3):242-51.

Awayn NH, Rosenberg MF, Kamis AB, Aleksandrov LA, Riordan JR, Ford RC. Crystallographic and single-particle analyses of native- and nucleotide-bound forms of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Biochem Soc Trans. 2005 Nov;33(Pt 5):996-9.

Rosenberg MF, Kamis AB, Aleksandrov LA, Ford RC, Riordan JR. Purification and crystallization of the cystic fibrosis transmembrane conductance regulator (CFTR). J Biol Chem. 2004 Sep 10;279(37):39051-7. Epub 2004 Jul 9.

Structures of related ABC transporters

Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL, Chang G. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science. 2009 Mar 27;323(5922):1718-22.

Ward A, Reyes CL, Yu J, Roth CB, Chang G. Flexibility in the ABC transporter MsbA: Alternating access with a twist. Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19005-10.

Dawson RJ, Locher KP. Structure of a bacterial multidrug ABC transporter. Nature. 2006 Sep 14;443(7108):180-5.

Models of CFTR

Mornon JP, Lehn P, Callebaut I. Molecular models of the open and closed states of the whole human CFTR protein. Cell Mol Life Sci. 2009 Nov;66(21):3469-86.

Huang SY, Bolser D, Liu HY, Hwang TC, Zou X. Molecular modeling of the heterodimer of human CFTR's nucleotide-binding domains using a protein-protein docking approach. J Mol Graph Model. 2009 Apr;27(7):822-8.

Mornon JP, Lehn P, Callebaut I. Atomic model of human cystic fibrosis transmembrane conductance regulator: membrane-spanning domains and coupling interfaces. Cell Mol Life Sci. 2008 Aug;65(16):2594-612.

Serohijos AW, Hegedus T, Aleksandrov AA, He L, Cui L, Dokholyan NV, Riordan JR. Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function. Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3256-61.

Callebaut I, Eudes R, Mornon JP, Lehn P. Nucleotide-binding domains of human cystic fibrosis transmembrane conductance regulator: detailed sequence analysis and three-dimensional modeling of the heterodimer. Cell Mol Life Sci. 2004 Jan;61(2):230-42.

Additional Information:

• NBD1 structures 
• SGX construct collection at DNASU 
• CFTR full-length and domain proteins (see CFTR Protein Sourcing) 
• RCSB Protein Data Bank

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Mucocilliary Clearance Consortium

The mission of the Mucociliary Clearance Consortium is to:

• Improve our understanding of how the airway environment (including airway surface liquid volume, ionic content, and glandular macromolecules) results in abnormal mucus and aberrant mucociliary transport, and determine the limits of CFTR, epithelial sodium channel, and other ion transporter activities required to maintain normal physiology;
  
  
• Examine whether mucin biogenesis and post-translational modification pathways are aberrant in CF, and determine their functional relationship to the ion transport environment; and
  
  
• Develop new preclinical and clinical measures of mucociliary clearance to allow a better understanding of this process, prioritization of therapeutic compounds under development, and evaluation of downstream effects elicited by ion transport modulators.

Consortium Membership

Suggested Reading:

Ion Transport, Mucus Secretion and Clearance

Zhang L, Button B, Gabriel SE, Burkett S, Yan Y, Skiadopoulos MH, Dang YL, Vogel LN, McKay T, Mengos A, Boucher RC, Collins PL, Pickles RJ. CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. PLoS Biol. 2009 Jul;7(7):e1000155. Epub 2009 Jul 21.PMID: 19621064

Ballard ST, Parker JC, Hamm CR. Restoration of mucociliary transport in the fluid-depleted trachea by surface-active instillates. Am J Respir Cell Mol Biol. 2006 Apr;34(4):500-4. Epub 2005 Dec 15.PMID: 16357366

Inglis SK, Corboz MR, Ballard ST. Effect of anion secretion inhibitors on mucin content of airway submucosal gland ducts. Am J Physiol. 1998 May;274(5 Pt 1):L762-6.PMID: 9612291

Joo NS, Wine JJ, Cuthbert AW. Lubiprostone stimulates secretion from tracheal submucosal glands of sheep, pigs, and humans. Am J Physiol Lung Cell Mol Physiol. 2009 May;296(5):L811-24. Epub 2009 Feb 20.PMID: 19233902

Choi JY, Khansaheb M, Joo NS, Krouse ME, Robbins RC, Weill D, Wine JJ. Substance P stimulates human airway submucosal gland secretion mainly via a CFTR-dependent process. J Clin Invest. 2009 May;119(5):1189-200. doi: 10.1172/JCI37284. Epub 2009 Apr 20.PMID: 19381016

Ianowski JP, Choi JY, Wine JJ, Hanrahan JW. Substance P stimulates CFTR-dependent fluid secretion by mouse tracheal submucosal glands. Pflugers Arch. 2008 Nov;457(2):529-37. Epub 2008 May 29.PMID: 18509672

Wu JV, Krouse ME, Wine JJ. Acinar origin of CFTR-dependent airway submucosal gland fluid secretion. Am J Physiol Lung Cell Mol Physiol. 2007 Jan;292(1):L304-11. Epub 2006 Sep 22.PMID: 16997881

Garcia MA, Yang N, Quinton PM. Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretion. J Clin Invest. 2009 Sep;119(9):2613-22. doi: 10.1172/JCI38662. Epub 2009 Aug 24. Erratum in: J Clin Invest. 2009 Nov;119(11):3497. PMID: 19726884

Mucus and Mucins

Kesimer M, Makhov AM, Griffith JD, Verdugo P, Sheehan JK. Unpacking a gel-forming mucin: a view of MUC5B organization after granular release. Am J Physiol Lung Cell Mol Physiol. 2010 Jan;298(1):L15-22. Epub 2009 Sep 25.PMID: 19783639

Kesimer M, Sheehan JK. Analyzing the functions of large glycoconjugates through the dissipative properties of their absorbed layers using the gel-forming mucin MUC5B as an example. Glycobiology. 2008 Jun;18(6):463-72. Epub 2008 Mar 13.PMID: 18339669

Sheehan JK, Kesimer M, Pickles R. Innate immunity and mucus structure and function. Novartis Found Symp. 2006;279:155-66; discussion 167-9, 216-9. Review.PMID: 17278393

Zhu Y, Ehre C, Abdullah LH, Sheehan JK, Roy M, Evans CM, Dickey BF, Davis CW. Munc13-2-/- baseline secretion defect reveals source of oligomeric mucins in mouse airways. J Physiol. 2008 Apr 1;586(7):1977-92. Epub 2008 Feb 7.PMID: 18258655

Davis CW, Dickey BF. Regulated airway goblet cell mucin secretion. Annu Rev Physiol. 2008;70:487-512. Review.PMID: 17988208

Kirkham S, Kolsum U, Rousseau K, Singh D, Vestbo J, Thornton DJ. MUC5B is the major mucin in the gel phase of sputum in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008 Nov 15;178(10):1033-9. Epub 2008 Sep 5.PMID: 18776153

Thornton DJ, Rousseau K, McGuckin MA. Structure and function of the polymeric mucins in airways mucus. Annu Rev Physiol. 2008;70:459-86. Review.PMID: 17850213

Novel Techniques and Protocols

Shikata H, McLennan G, Hoffman EA, Sonka M. Segmentation of Pulmonary Vascular Trees from Thoracic 3D CT Images. Int J Biomed Imaging. 2009;2009:636240. Epub 2009 Dec 14.PMID: 20052391

Li B, Christensen GE, Hoffman EA, McLennan G, Reinhardt JM. Pulmonary CT image registration and warping for tracking tissue deformation during the respiratory cycle through 3D consistent image registration. Med Phys. 2008 Dec;35(12):5575-83.PMID: 19175115

Tang BC, Dawson M, Lai SK, Wang YY, Suk JS, Yang M, Zeitlin P, Boyle MP, Fu J, Hanes J. Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19268-73. Epub 2009 Nov 9.PMID: 19901335

Suk JS, Lai SK, Wang YY, Ensign LM, Zeitlin PL, Boyle MP, Hanes J. The penetration of fresh undiluted sputum expectorated by cystic fibrosis patients by non-adhesive polymer nanoparticles. Biomaterials. 2009 May;30(13):2591-7. Epub 2009 Jan 26.PMID: 19176245

Lai SK, Wang YY, Wirtz D, Hanes J. Micro- and macrorheology of mucus. Adv Drug Deliv Rev. 2009 Feb 27;61(2):86-100. Epub 2009 Jan 3. Review.PMID: 19166889

Donaldson SH, Corcoran TE, Laube BL, Bennett WD. Mucociliary clearance as an outcome measure for cystic fibrosis clinical research. Proc Am Thorac Soc. 2007 Aug 1;4(4):399-405. Review.PMID: 17652507

Donaldson SH, Bennett WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med. 2006 Jan 19;354(3):241-50.PMID: 16421365

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CF Biomarker Consortium 

The mission of the CF Biomarker Consortium is to identify and validate CF biomarkers to advance research and improve clinical care for individuals with CF. The focus of the Biomarker Consortium is in the areas of identifying biomarkers that:

• Track and predict disease progression (including early lung disease, lung function decline, and pulmonary exacerbations);
• Detect improved function of CFTR for new candidate targets and pathways for CF; and
• Validate preclinical animal model systems.

Consortium Membership

Suggested Reading:

Ashlock MA, Olson ER. Therapeutics development for cystic fibrosis: a successful model for a multisystem genetic disease. Annu Rev Med. 2011 Feb 18;62:107-25.

Hug MJ, Derichs N, Bronsveld I, Clancy JP. Measurement of ion transport function in rectal biopsies. Methods Mol Biol. 2011;741:87-107.

Rowe SM, Clancy JP, Wilschanski M. Nasal potential difference measurements to assess CFTR ion channel activity. Methods Mol Biol. 2011;741:69-86.

Zemanick ET, Sagel SD, Harris JK. The airway microbiome in cystic fibrosis and implications for treatment. Curr Opin Pediatr. 2011 Jun;23(3):319-24.

Zemanick ET, Wagner BD, Sagel SD, Stevens MJ, Accurso FJ, Harris JK. Reliability of quantitative real-time PCR for bacterial detection in cystic fibrosis airway specimens. PLoS One. 2010 Nov 30;5(11):e15101.

Clancy JP, Rowe SM, Accurso FJ, Aitken ML, Amin RS, Ashlock MA, Ballmann M, Boyle MP, Bronsveld I, Campbell PW, Deboeck K, Donaldson SH, Dorkin HL, Dunitz JM, Durie PR, Jain M, Leonard A, McCoy KS, Moss RB, Pilewski JM, Rosenbluth DB, Rubenstein RC, Schechter MS, Botfield M, Ordoñez CL, Spencer-Green GT, Vernillet L, Wisseh S, Yen K, Konstan MW. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax. 2011 Aug 8. [Epub ahead of print]

Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordoñez CL, Campbell PW, Ashlock MA, Ramsey BW. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010 Nov 18;363(21):1991-2003.

Sagel SD, Gibson RL, Emerson J, McNamara S, Burns JL, Wagener JS, Ramsey BW; Inhaled Tobramycin in Young Children Study Group; Cystic Fibrosis Foundation Therapeutics Development Network. Impact of Pseudomonas and Staphylococcus infection on inflammation and clinical status in young children with cystic fibrosis. J Pediatr. 2009 Feb;154(2):183-8. Epub 2008 Sep 25.

Sagel SD, Chmiel JF, Konstan MW. Sputum biomarkers of inflammation in cystic fibrosis lung disease. Proc Am Thorac Soc. 2007 Aug 1;4(4):406-17.

Protocols

Standard operating procedures (SOPs) relevant to biomarker and other clinical studies are available from the TDN Coordinating Center for purposes of protocol development or other general reference needs. Please contact TDNCC@seattlechildrens.org for more information.

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