Development of biological tools for the study and modulation of ion channels.

Ion channels are proteins that can span the cell membrane. They are said to be active when the ion channel pore is open, permitting charged ions such as sodium, potassium, calcium, or chloride to flow from one side of the membrane to the other. There are many different types of ion channel and their activity determines how the cell responds to external and internal stimuli. They are responsible for generating and sending nerve impulses, the beat of the heart, hormone release, and muscle contraction, to name a few examples. There are hundreds of different types of ion channel protein, but relatively few chemicals that can be used change the behaviour of the ion channel. This makes some experiments difficult because it is difficult to home in on the specific ion channel that is responsible for the biological event that a researcher is investigating. It also means that there are few starting points for the development of new medicines that act on ion channels. Because it is not possible to directly monitor ion channel activity biochemically, it is also difficult to conduct experiments and develop methods to screen thousands of chemicals for new modulators. This project aims to meet these needs by identifying small proteins that stick to ion channels and those that change ion channel behaviour.

If successful, this technology will generate tools and resources that will prove invaluable to ion channel researchers in the U.K. and internationally, and will have many different applications in biotechnology.

Ion channels are one of the largest super-families of proteins encoded by the human genome and are central to excitatory, homeostatic, and signalling processes within and between cells. As such, they remain one of the important classes of protein that are targets for drug action for the treatment of chronic human disorders in most of the major therapeutic areas. Studying mammalian ion channels, from structure to cellular and whole organism function, is technically challenging and has been hampered by a lack of reagents that are able to probe the location and functional role of each individual channel type. Furthermore, and despite advances in ion channel screening technology, inadequate platforms exist for high throughput primary screens for most types of channel.
We have developed a new library of artificial binding proteins (Adhirons) of high complexity ca. 3x10^10 in a phage display format. The library presents two randomised variable regions that are available for binding to target proteins. We intend to demonstrate the potential of our functionally active Adhirons as reagents for studying ion channel function and cell biology. We will select Ahdirons that bind to ion channels in their natural environment, the cell membrane, and then interrogate whether they regulate ion channel function and/or are suitable as detection tools in fluorescence or immunoassays. This will provide the necessary protocols and tools for studying a highly important yet under-exploited family of proteins.
Novel reagents developed as a result of this project have significant research and commercial potential and can be used in diverse applications to advance ion channel and pharmaceutical science. In particular, they have immediate application in cell biology, target validation, cell-based assays that can be adapted for high-throughput screening, biomarker detection and visualisation, crystallography, and targeted delivery. These may also form the basis of biopharmaceutical therapies.

The impact activities will be coordinated by the investigators with assistance from Dr Kate Langton, Innovation Manager for the Pharmaceutical and Biopharmaceutical Innovation Hub.

1. To continue to align the research programme with end-user needs
The pharmaceutical and biopharmaceutical industry has been identified as one of the main beneficiaries of the novel tools that will be produced through this research. We have already discussed this project with staff from one UK-based pharmaceutical company in our network who have expressed an interest in future development and collaboration, should this project be successful. The models developed during this project, therefore, must meet the needs of this user-group if the tools are to be adopted in the industry as a key technology for studying ion channel function. The research programme therefore has industrial interest and we will work closely with these stakeholders to align the development to fit their needs. Further activities that will be carried out to understand the needs of this community include visits to additional potential end-users.

2. To define a pathway to commercialisation of the novel tools
To realise the full value of the tools developed during the programme requires their commercial availability. Therefore the definition of a pathway to commercialise the tools is a key output of the project. To achieve this we will immediately work closely with Commercialisation Services at Leeds to protect IP, where appropriate, and to develop an effective pathway to commercialisation (e.g. spin-out or licensing) and business model.

3. Dissemination of research and public understanding of science
Dissemination of the project outputs is critical to publicise the availability of the tools, and to strengthen the perceived utility of the new technologies. We will host an ion channel workshop with our local academic and industrial partners to provide training information about the new technology, and demonstrate its value to the ion channel community. The benefit to the development of new tools, as well as the potential impact for the public, will also be captured in separate podcasts that will be uploaded to appropriate websites (e.g. University YouTube channel). This will be supported by activities such as press releases by University of Leeds to ensure maximum exposure of the podcast. Additionally we will publish the research and work with the University of Leeds Press Office to issue further press releases to coincide with high-impact publications, and we will continue to engage with the general public (eg education conferences; Café Scientifique, Headingley, Leeds).