Chloride intracellular Channel 4 as a therapeutic target in the development of pulmonary arterial hypertension

Abstract

Pulmonary Arterial Hypertension (PAH) is a high-mortality disease centred on the progressive dysfunction of the right ventricle, as a result of pulmonary artery lumen narrowing and increased pulmonary vascular resistance. Chloride intracellular channel (CLIC) 4 has been recently suspected to play a role in the development of PAH pathogenesis via the propagation of vascular remodelling, a hallmark of PAH. CLIC4's involvement is linked to a newly-hypothesised CLIC4/Arf6 pathway, involving the protein Arf GTPase-activating protein (GIT) 1. This thesis shows the investigation into CLIC4 interactions with inhibitor Digoxin, and GIT1, which was modelled by assigning CLIC4 residues to a 2D Heteronuclear Single Quantum Coherence (HSQC) NMR spectrum. The results allowed a binding site on CLIC4 to be predicted manually and computationally, and CLIC4-GIT1 interactions were determined which strongly suggests CLIC4:GIT1 interactions in vivo. Overall, this thesis provides evidence of CLIC4's involvement in vascular remodelling pathways, and its viability as a therapeutic target and supports the novel Arf6/CLIC4 pathway believed to propagate PAH development. With this, the study provides new ideas into combatting PAH development, in a bid to reduce PAH-related mortality