Adenosine 5 -triphosphate (ATP) was discovered in muscles in 1929, and it was soon realised to be the key for energy production inside cells. But, as is often the case, the same molecule has an important role outside cells and is used to signal between cells. The cell surface receptors for ATP, known as P2X receptors, are proteins with a hole down the middle: they acts as gates that allow small ions to cross the membrane when ATP binds to the receptor. This in turn leads to changes in cell behaviour. In fact, it is now known that these responses to ATP regulate diverse physiological processes in mammals, including taste, bladder emptying, oxygen sensation, inflammation and pain. ATP signaling by P2X receptors therefore represents a novel target for disease involving pain and inflammation. To understand how P2X receptors work, it is important to understand how they are regulated, and to discover the further effects of P2X receptor activity. But such studies have been difficult to perform because P2X receptors had not been found in simple model organisms suitable for laboratory studies. Recently, we discovered that P2X receptors are present in the social amoebae, Dictyostelium discoideum. Dictyostelium is used to study many processes in cell and developmental biology, due to its relative simplicity and the ease with which genetic and biochemical studies can be carried out. We were surprised to find that one Dictyostelium P2X receptor actually regulates responses to ATP inside cells, rather than at the cell surface. But we believe that this action is not related to energy metabolism: rather, the receptors are required for the cells to adapt to the stress of being submerged in water. As Dictyostelium cells normally live in the soil, this is likely an important adaptation for their survival. Most importantly, these findings will allow us to address how P2X function is regulated. Firstly, we will use cutting edge genetic and biochemical techniques to identify other proteins that are required to regulate receptor activity in Dictyostelium. Secondly, we will determine the role of the other four P2X receptors and compare the ATP responses of these receptors to those seen with mammalian P2X receptors. Since the basic mechanism of operation of P2X receptors is conserved from amoeba to man, we will be able to advance our understanding of P2X receptor function, regulation and structure in all animal species.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

The proportion of elderly people in our society is increasing. As a result there is an increase in the number of people with age related degenerative diseases that cause dementia. It is known that dementia, in certain circumstances, can be inherited and run in families. Approximately 750,000 people in the UK have some form of dementia, the most common and widely known is Alzheimer?s disease. Thankfully, a lot of progress has been made in understanding the genetic cause of Alzheimer?s disease. The second most common form of dementia is called frontotemporal dementia or FTD. It can affect people?s behaviour and ability to speak. About half of all people with FTD have other family members with this disease, therefore, there is a large inherited (genetic) reason for the development of this disease. We know around 10% of cases of FTD are caused by errors in a gene called tau, however, we know nothing about the remaining 90%. There are reports of families with FTD showing there is a gene problem on chromosome 17, where the tau gene lies. However, nobody has been able to find any errors in the tau gene in these families. I will analyse the entire tau gene, more thoroughly than has been done before, and will check nearby genes to identify the disease causing error. The second part of my project is as follows; By testing a large collection of FTD patients collected from around Manchester I have shown there is a gene causing FTD with motor neuron disease on chromosome 9, consistent with a report from the US. By identifying common regions of chromosome 9 shared by patients from Manchester, and screening the genes within these regions, I hope to identify the disease-causing gene. Finally, it has been reported that errors in a gene called VCP can cause a bone disease and FTD in some patients. I will screen the Manchester FTD patients to see if VCP is causing disease in any of them. In summary, it is important to find genes causing FTD because it is a common form of dementia with a large genetic component to its cause. By identifying these genes we will find the primary cause of, and gain understanding to, the biological problem reason of disease. This knowledge will help in diagnosis and in the development of systems to produce a treatment, which will ultimately help people affected by this illness.

The Facility offers access to state-of-the art experimental techniques for multi-frequency continuous wave and pulsed EPR spectroscopy, and associated methods, and data modelling. The Facility is located in the Photon Science Institute at the University of Manchester and further specialised experiments are available through partners at the University of Oxford. The Facility handles a wide range of sample types, including samples that are sensitive to temperature, atmosphere, light, solvent loss, and a wide range of sample hazards, including toxic and low-level radioactive materials. Industrial usage can also be arranged; however, a charge is applied. It is the policy of the Centre that suppliers of samples are encouraged to visit the Centre and to gain “hands on” experience. For further information see: http://www.chemistry.manchester.ac.uk/our-research/facilities/epr/ To contact the National EPR Facility and Service, please email: epr@manchester.ac.uk

Cough is the most common symptom for which patients seek medical advice and it is estimated that cough costs the UK economy £1 billion each year. Despite this we know very little about the processes which lead to coughing and we do not have effective treatments for cough. Patients with chronic cough describe themselves as very sensitive to smoky atmospheres and temperature changes and even talking and laughing can trigger coughing. Much more is known about the pain pathways and how they become too sensitive, causing chronic pain. This programme of work draws on this knowledge to better understand how the nerves involved in the cough reflex can become over sensitive. New techniques will be developed for testing new treatments for this very common and troublesome symptom.