Characterisation and Correction of the F508del-CFTR defect

Abstract

Cystic Fibrosis is an autosomal recessive disease that is characterised by conditions present throughout the body. The majority of cystic fibrosis cases are caused by the deletion of phenylalanine at position 508 in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). A large amount of research, from across a number of fields, has gone into correcting the defect caused by the mutation. The work in this thesis continues this principle of research providing a multi-disciplinary approach to providing insight into the mechanism of disease and solving the issue of F508del-CFTR. There exists limited pharmacological options for cystic fibrosis patients who are homozygous for the F508del mutation, with current treatments currently exorbitantly expensive, providing limited rescue and still leaving patients with a greatly reduced quality of life; this thesis provides an assay by which to develop novel compounds, or investigate existing pre-clinical compounds, which would benefit patients in the future. The method is validated by determination of the stability impacts of a novel biosensor and novel pre-clinical corrector, as well as the testing of an FDA approved library of existing widely used drugs. Recently, the cystic fibrosis research field has been bolstered by the publication of several cryo-electron microscopy structures showing CFTR in its various states. Work in this thesis aims to provide insight into the differences of these states, via limited exposure to proteases, as well as provide further insight into the protein population that is recognised by cell quality control machinery and degraded

Date of Award	31 Dec 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Robert Ford (Supervisor) & David Thornton (Supervisor)