Modulation of CFTR stability and function from the extracellular space

Objective

The CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) is a unique ABC protein functioning as a chloride channel. It consists of two transmembrane and two nucleotide binding domains, and a regulatory region. The cftr gene is mutated in cystic fibrosis, an inherited disease of high morbidity and mortality mostly affecting people with European ancestors. So far more than 1,500 mutations are known affecting the stability or the function of the protein that results in the lack of functional channels in the cell membrane. This leads to imbalanced water and salt homeostasis affecting the function of all organs with secretory epithelia. Therefore it is important to develop therapeutic agents to stabilize CFTR and restore its function. This is being done by blind screening resulting in compounds that are hydrophobic and act on either the transmembrane or intracellular parts of the protein. In this study we aim to modulate the stability and function of CFTR from the extracellular side. The advantage of this approach is the targeting of the hydrophilic extracellular loops that enable structural studies and design of water soluble drugs with advantageous toxological properties. We will employ cutting-edge computational approaches combined with solid experimental methods to gain insights in the structure and dynamics of the larger extracellular loops in CFTR. The effects of the extracellular loops on the conformation of the transmembrane region and the protein function will be studied that will establish a basis for rational drug design. Our preliminary results indicate that the extracellular loops possess stable secondary structural elements and changes in their conformation can either stimulate or inhibit the protein function. Together, the extracellular loops will provide a focused target to restore CFTR stability and function. Moreover, this approach can be also applied to rationally modulate the function of other ABC proteins involved in human diseases.

Fields of science (EuroSciVoc)

CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.

• medical and health sciences basic medicine medicinal chemistry
• natural sciences biological sciences biochemistry biomolecules proteins
• natural sciences biological sciences genetics mutation
• natural sciences biological sciences genetics nucleotides
• medical and health sciences basic medicine physiology homeostasis

Keywords

Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)

• ABC proteins
• NMR
• ab initio folding
• channel function
• chemical cross-linking
• cystic fibrosis
• molecular dynamics
• multi-drug transporters
• therapeutic target
• transmembrane proteins

Programme(s)

Multi-annual funding programmes that define the EU’s priorities for research and innovation.

• FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Topic(s)

Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.

• PEOPLE-2007-4-3.IRG - Marie Curie Action: "International Reintegration Grants"

Call for proposal

Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.

FP7-PEOPLE-IRG-2008
See other projects for this call

Funding Scheme

Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.

MC-IRG - International Re-integration Grants (IRG)

Coordinator