Saturday, 28 February 2015

My successful SRC grant application

As the Cystic Fibrosis Trust announces a call for applications to form up to three more Strategic Research Centres, Dr David Sheppard of the University of Bristol explains how he went about submitting a successful SRC application.

As a scientist based at a UK university, a significant part of my time is spent applying for research funding. This funding provides salaries and bursaries for the research fellows and students that I have the privilege to work with. These highly creative individuals labour for long hours in the lab to understand better how the cystic fibrosis transmembrane conductance regulator (CFTR) works, how it goes wrong in cystic fibrosis (CF) and how drugs repair the faulty CFTR. Funding also covers the cost of all the “stuff” required to do experiments in the lab. In our case, this involves some very expensive equipment needed to monitor CFTR activity as tiny electrical currents, paraphernalia to grow cells and a battery of chemicals to stimulate CFTR and manipulate its activity. Simply put, without funding there is no research.

With my research focusing on CFTR, the CF Trust is the major funder of our work. I’m extremely grateful to the Trust for the funding that I have received over the last 20 years. The output of our research has included knowledge of how gating mutations (eg, G551D) interfere with CFTR function and the action of chemicals that act as CFTR potentiators. This information has helped the development of transformational drugs that treat the root cause of CF.

When the CF Trust announced its new research strategy in April 2013, I began to think about how to apply for a Strategic Research Centre (SRC) grant from the Trust. SRCs are virtual research centres of excellence that bring together research groups from the UK and overseas to tackle a fundamental problem in CF.

What problem to address? Great progress has been made in our understanding of F508del, the most common CF mutation, leading to clinical trials of CFTR correctors and potentiators. While very encouraging, data from the lab and clinic argue that better drugs are required to fully rescue F508del-CFTR. By focusing on F508del-CFTR, the SRC would have the potential to benefit the largest number of individuals living with CF.

Today, most research is multidisciplinary, meaning that methods from different research disciplines (eg, biochemistry and physiology) are used together to solve specific questions. While some labs successfully apply different research methods, many specialise. My own work is very highly specialised, focusing on how individual CFTR proteins work. To apply successfully for SRC funding, we would need to collaborate actively with other groups expert in studying CFTR structure, how it is made inside cells and delivered to its correct cellular location. We would also need help from pharmacologists expert in testing large numbers of chemicals for drug action.

Early in planning the application, I approached Professor Bob Ford from the University of Manchester. Bob has been at the forefront of efforts to identify the structure of CFTR. This work is fundamental to understand CFTR and its dysfunction in CF. I also approached Professor Ineke Braakman from Utrecht University in The Netherlands. Ineke and I had previously made plans to study how CFTR matures inside cells to become a gated pathway for chloride movement. When compared with other methods to study CFTR activity, those used by my Bristol colleagues are notoriously slow. Two groups studying CFTR activity would therefore be advantageous for an SRC application. Because of her expertise in studying how CFTR flutters open and closed, I approached Dr Paola Vergani at University College London. I was delighted that Bob, Ineke and Paola all readily agreed to participate in the SRC application.

Plans for the SRC were finalised at a conference in Malta organised by the European CF Society last March. Because the meeting was so intense, it was not until the day after the meeting that Bob and I finally found time to discuss, in detail, plans for the SRC, especially how the different project partners would work together to address our research goals. During these discussions, we recognised that the SRC would require a group expert in the pharmacology of CFTR. With his wide-ranging expertise in studies of drugs targeting CFTR, we both agreed that Professor Frédéric Becq from Poitiers University in France was an excellent choice. Returning to Bristol, I telephoned Frédéric to invite him to join; he agreed immediately. With the team recruited, we then set about writing the application. The initial application went smoothly, but the full application involved a lot more work; not for the first time lots of late nights and early mornings close to the deadline!

Bob, Ineke, Paola, Frédéric and I were delighted to learn that our SRC application was successful. We are excited about the studies of F508del-CFTR that we have planned. We believe strongly that they will inform the development of new drugs to benefit the majority of individuals living with CF.

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