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Title: Modulation of proteostasis for the efficient intracellular transport of the AF508 mutant of cystic fibrosis transmembrane conductance regulator
Author: Hegde, Ramanath Narayana
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2013
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The cystic fibrosis transmembrane conductance regulator (CFTR) L\F508 mutant (L\F508CFTR) contributes to 70% cystic fibrosis cases, and it undergoes aberrant proteostasis, misfolding, intracellular retention and degradation. Targeting L\F508CFTR proteostasis components has been successful in the partial rescue of L\F508CFTR at the plasma membrane. Drug screening has identified correctors which rescue a fraction of the L\F508CFTR at the plasma membrane. However, all these correctors are marginally effective and are not therapeutically viable. This thesis project used a systems-biology-based meta-analysis approach of gene expression induced by corrector drugs to infer their mechanisms of action, and this led to the identification of a group of genes that are commonly regulated by many of these drugs. These groups of genes were used to determine the networks/ pathways/ molecules that might be correlated with their correction. These include components of RNA processing, the cell cycle, ubiquitin ligases, and kinases, many of which have led to patiial rescue of L\F508CFTR when they have been depleted by RNA interference. FUlihermore, two of these pathways are characterised here: the MAP3K II-JNK cascade and the CaM kinase (CAMKK2) cascade. Several members of these cascades rescued L\F508CFTR. The MAP3Kll -initiated pathway has a role in ER-associated degradation and plasma-membrane stability of L\F508CFTR. MAP3K 11 also appears to link oxidative stress and inflammation to intracellular proteostasis of L\F508CFTR. Some upstream activators and downstream targets of MAP3K 11 can also rescue L\F508CFTR. Drugs that inhibit the MAP3K II-JNK cascade rescued functional L\F508CFTR at the plasma membrane. Combinations of these drugs with the previously clinically studied corrector pharmacochaperone YX-809 led to a high level of correction of L\F508CFTR, which was much greater than for YX-809 alone. Many candidate genes and drugs that are identified in the current study open the way to the development of the new efficient therapeutic agents for cystic fibrosis caused by the L\F508 mutation. .
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available