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Personalised therapies for all : Targeting alternative chloride channels in Cystic Fibrosis
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Cystic Fibrosis (CF) is a life-shortening genetic disorder caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, which encodes a cAMP-regulated chloride (Cl−) and bicarbonate (HCO3−) channel expressed at the apical membrane of epithelial cells. Faulty CFTR causes unbalanced salt and fluid transport, resulting in dehydrated lung secretions, enhanced mucus viscosity, and impaired mucociliary clearance, culminating in progressive obstruction of the airways. Other organs such as the intestine, reproductive tissues, and pancreas are also affected in CF.
Despite recent progress in the development of therapies targeting the root cause of the disease, several people with CF, namely the ones with rare or “unrescuable” mutations, still lack effective treatments. An alternative would be to develop “mutation-agnostic” therapies, namely through the modulation of other (non-CFTR) anion channels/transporters. The main goal of this work was to understand if and how these alternative channels can be used as therapeutic targets in CF.
TMEM16A is the major contributor to Ca2+-activated Cl– secretion in the airways and has the potential to bypass defective CFTR-dependent Cl– secretion. Here we developed a screening platform that was used to identify novel modulators of TMEM16A trafficking and function (Chapter 1). We have also demonstrated an overlap between Ca2+ and cAMP-induced currents, implying an intimate relationship between TMEM16A and CFTR (Chapter 2). Furthermore, another member of the TMEM16 family, TMEM16F, was also shown to regulate CFTR trafficking and function (Chapter 2).
Another interesting alternative target is SLC26A9, a constitutively active Cl– transporter. We showed that CFTR expression, function, and rescue by modulators are dependent on SLC26A9 expression levels (Chapter 3). Finally, we have also identified regulators of SLC26A9 trafficking, that can potentially be used as novel therapeutic targets in CF therapies (Chapter 3).
Taken together, our findings support a role for TMEM16A and SLC26A9 as clinically relevant disease modifiers and promising therapeutic targets to circumvent deficient Cl– secretion in CF.
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Palavras-chave
Anoctamina 1/TMEM16A canal de cloreto ativado por cálcio CFTR Fibrose Quística SLC26A9 transportador de cloreto tráfego intracelular Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator TMEM16A anoctamin 1 Ca2+-activated Cl− channel solute carrier family 26, member 9 Cl− transporter intracellular traffic