Tools for the study and modulation of transmembrane movement of bicarbonate
Project ID: 2228cd1328 (You will need this ID for your application)
Research Theme: Healthcare Technologies
UCL Lead department: Division of Biosciences
Lead Supervisor: Paola Vergani
Project Summary:
Why is this research important? The CFTR channel regulates flow of chloride (Cl-) and bicarbonate (HCO3-) ions across epithelia. Recent studies have highlighted the crucial physiological role of transepithelial movement of HCO3-. HCO3- in bile and pancreatic juice is required for the breakdown and absorption of fats. In airway and gut secretions, it controls antimicrobial effects and mucus release and fluidity, affecting immune system-microbiome interactions. New CFTR-targeting drugs, developed to treat cystic fibrosis, primarily optimise Cl- conductance. Yet in some tissues CFTR mostly mediates HCO3- flow. The project will deliver chemical tools for drug development and for investigating this key, yet understudied, physiological process.
Who will you be working with? You will be part of two labs: one with expertise in supramolecular chemistry and small-molecule ion carrier testing; the other in CFTR physiology and pharmacology.
What will you be doing? You will generate a small chemical library of ionophores, using synthetic organic chemistry and metal-coordination driven self-assembly. You will then screen these molecules, and others, for selective HCO3-/Cl- transport activity in simple synthetic lipid vesicle systems, using a high-throughput ion transport assay. Iterative rounds of hit identification, chemical modification and re-testing will optimise selectivity for HCO3- over Cl-. You will further characterise the most promising anionophores in a cell-based fluorescence assay, to compare ionophore- and protein-mediated transmembrane anion flow and improve the assay’s accuracy in quantifying selective HCO3- transport in a cellular context. In a second step, you will develop anionophores with diverse tissue-targeting properties. Modular attachments will alter and control the hydrophobicity of molecules, in response to distinct conditions encountered (low gastric pH) and to external stimuli (light/ heat).
Who are we looking for? A person enthusiastic about applying fundamental chemical knowledge and skills; curious about understanding physiological processes in depth; eager to generate tools for developing better drugs.