Hypertension is a very common health problem, and is perceived by the public as an important risk factor for cardiovascular disease. Better understanding of how genetic risk of hypertension interacts with environmental factors such as dietary sodium is important if members of the public are to be persuaded to alter lifestyle. We have already had experience of the interest that the lay public has in this area through the high level of participation in the Bright Study. The development of the UK Biobank programme over the next few years will offer an important DNA resource that will allow any key candidate genes that might have an important environmental interaction for a common disease to be studied in greater detail, and we propose to ensure that our links with the Biobank proposal through local and national collaborations are exploited in due course.

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 intestine is continually exposed to viruses, bacteria and parasites which threaten its function and against which we must defend ourselves. This is the role of the protective immune response and to combat infection, the intestine contains parts of the immune system. However, the majority of the food we eat is also ?foreign? to our immune system, as are the huge numbers of harmless bacteria (commensals) that live normally in our intestines and are essential for life. It is important that we do not attempt to make protective immune responses against these useful materials, as this can lead to severe intestinal disorders such as coeliac disease and Crohn?s disease. Indeed, the immune system normally becomes unresponsive (tolerant) to these materials as it has evolved mechanisms for distinguishing between dangerous and harmless materials. It is important to understand how this happens, not only to have a better chance of treating intestinal disease, but also because there is a great need for new vaccines to combat infections of the intestine. In addition, it may be possible to treat a number of inflammatory conditions such as diabetes and rheumatoid arthritis by exploiting this ability of immune system to become tolerant to ingested materials. A considerable amount is already known about the cellular processes involved and it now seems clear that the signals dictating how a particular population of T lymphocytes (those carrying the CD4 marker) responds may be very different in cells reacting to dangerous versus harmless materials. Thus, it may be possible to target some of these signals to deliberately switch on or off immune responses in the intestine. However, progress in this area has been limited by the fact that it is extremely difficult to identify directly those CD4+ T cells that respond. Moreover, study of the signals usually requires cells to be removed from the immune system and submitted to harsh biochemical processes. We have now developed new models that allow normal and mutant antigen specific T lymphocytes to be tracked and characterised in the intact immune system with highly sensitive laser-driven microscopy techniques that can assess such signals in individual cells. By analysing these events in situ, we hope to be able to identify precisely molecules that might prove useful in treatment of disease and in vaccine development.

Worldwide, 8 million deaths have been attributed to high blood pressure (hypertension) per year. This accounts for at least half of all annual deaths from cardiovascular disease (stroke, heart attacks). Despite considerable research, the underlying causes of high blood pressure in most cases remain unclear. This proposal focuses on steroid hormones produced by the human adrenal gland and uses a number of techniques to examine their role in hypertension and cardiovascular disease. In particular, the effect of variation within genes that control the production of steroid hormones will be explored in a cohort of normal volunteers in order to clarify further the genetic basis of hypertension caused by excess of a key steroid hormone, aldosterone. The potentially harmful effect of this hormone on heart structure and function will also be investigated in patients with hypertension due to aldosterone excess using detailed magnetic resonance imaging scans. Finally, how steroid hormones interact with other factors including diet and salt intake to regulate blood pressure levels will also be explored in a large group of patients from different ethnic backgrounds. The planned studies should result in a better understanding of mechanisms that lead to hypertension and cardiovascular disease and more effective targeting of treatments as well as earlier identification of those most at risk of developing hypertension and its associated problems.