Linking the lipid-sensing TMEM16A channel with lysosomal lipid storage mechanisms: implications for drug discovery
Award Number
BB/T007664/1Status / Stage
ActiveDates
1 October 2020 -30 September 2023
Duration (calculated)
02 years 11 monthsFunder(s)
BBSRC (UKRI)Funding Amount
£444,774.00Funder/Grant study page
BBSRC UKRIContracted Centre
University of OxfordPrincipal Investigator
Dr Paolo TammaroPI Contact
paolo.tammaro@pharm.ox.ac.ukWHO Catergories
Understanding Underlying DiseaseDisease Type
Dementia (Unspecified)CPEC Review Info
| Reference ID | 721 |
|---|---|
| Researcher | Reside Team |
| Published | 07/07/2023 |
Data
| Award Number | BB/T007664/1 |
|---|---|
| Status / Stage | Active |
| Start Date | 20201001 |
| End Date | 20230930 |
| Duration (calculated) | 02 years 11 months |
| Funder/Grant study page | BBSRC UKRI |
| Contracted Centre | University of Oxford |
| Funding Amount | £444,774.00 |
Abstract
Chloride channels coded by the TMEM16A gene support a plethora of physiological processes and are potential drug targets. Thus far, however, the pharmacology of these channels has been restricted to compounds with low potency and poor specificity. The recent elucidation of the TMEM16A structure offers hope for improved understanding of its function and the development of better small molecule modulators. The structure of TMEM16A suggests an unprecedented exposure of the ion permeation pathways to the lipids of the plasma membrane. Consistent with this, we found that the TMEM16A channel (i) is regulated by endogenous signalling lipids as well as dietary fatty acids; (ii) is affected by alterations of the function of the lysosomal lipid transporter NPC1; and (iii) has a sensitivity to pharmacological modulators that depends on the lipid composition of the membrane. We therefore hypothesise that TMEM16A serves as a lipid sensor that couples changes in lipid metabolism with changes in cell electrical activity. Our aims are to: (i) understand the cellular and molecular properties of TMEM16A that enable it to respond to a variety of lipids and (ii) to exploit knowledge of these mechanisms to enable rational drug design of small molecules that control TMEM16A function for potential therapeutic benefit. This will be achieved by: – Systematically determining the classes of lipids that regulate TMEM16A function. – Utilising lipids and existing tool compounds as starting points for the identification of new modulators of TMEM16A. – Examining the effects of lipids and new modulators in native tissues to validate the potential of these agents to treat NPC1 and related diseases. This study aims to leverage the basic bioscience excellence of the academic partners with the state of the art platforms for drug discovery at Autifony, to reveal novel aspects of cell biology and translate this knowledge to impact human and animal health, and wellbeing.
Aims
Our aims are to: (i) understand the cellular and molecular properties of TMEM16A that enable it to respond to a variety of lipids and (ii) to exploit knowledge of these mechanisms to enable rational drug design of small molecules that control TMEM16A function for potential therapeutic benefit.