One basic feature of cells is their ability to grow and divide. The production of proteins, essential cell components that represent a significant proportion of the cell mass, is essential for cell growth. The ribosome is a molecular factory in the cell responsible for the synthesis of proteins. The cell regulates protein production by changing the activity and/or the levels of ribosomes. In cell transformation, the initial stage in the generation of tumours, the basic regulation of cell growth and division is lost allowing the cell to continue growing unchecked. It has recently been shown that many proteins that either cause or regulate cancer are also linked to the regulation of protein synthesis in the cell. This often involves the regulation of the synthesis of new ribosomes in a specific compartment in the cell known as the nucleolus. The production of the ribosome is a highly complicated process that is at present poorly understood. The cell has natural tumour suppressive agents such as the protein p53. The activation of this protein inhibits cell growth and division and is linked to the function of the nucleolus. We have found that chemical inhibitors that activate p53 also block the production of ribosomes. We propose to investigate the mechanisms by which these inhibitors block to production of ribosomes. The information gained from this approach will provide important information on how the cell activates the tumour suppressor p53. This research will provide important information on how the cell regulates cell growth and division and should provide new targets for anti-cancer therapeutics.

Neurological disorders such as Alzheimer?s disease and dementia with Lewy bodies affect large numbers of individuals in the UK and represent some of the major health burdens in developed countries. For example Alzheimer?s affects over 400,000 people in the UK and the numbers of people with the disorder are expected to rise substantially in coming years. Whilst considerable advances have been made in our understanding of disorders that affect brain function, we still need to identify the underlying causes so that we can find new treatments. Collection of brain tissue from donors at death represents one of the very few ways that we can investigate the biochemistry and pathology of neurodegenerative disorders. It is not generally possible to take brain tissue from live donors and animal models can only mimic certain aspects of the human disorder. Post mortem tissue research is therefore our best avenue to understanding these conditions. By studying such tissue samples it is possible to identify the changes that give rise to conditions such as Alzheimer?s disease, Parkinson?s disease, depression and motor neurone disease. This project aims to collect brain tissue from donors from a wide range of neurological and psychiatric disorders, focussing on dementia and neurodegenerative disease, for distribution to both the national and international research community through a wide network, managed in collaboration with the UK Medical Research Council. This will ensure that as many research projects as possible can be undertaken on the samples, thereby increasing the opportunities for identifying treatments for these disorders. All donors will have been seen in a recognised specialist clinic and will have agreed to donate tissue before their death, having been informed of all procedures. Next of kin and other involved parties will be included in these discussions. The project has already received formal Ethical Approval and we have been making this type of request to patients and their families for many years without experiencing any adverse reactions. Indeed most people find this a welcome opportunity to contribute to an important research effort. Our long term aim is to contribute as widely as possible to the national programme of brain research into neurological and psychiatric disorders and advance our understanding of the causes of these disorders, with the long term aim of identifying treatments.

All pregnant women are offered scans at 12 and 20 weeks of pregnancy to confirm the dates and detect fetal abnormalities, many of which are due to chromosome imbalances (i.e. gains or losses of part or all of a chromosome). Babies with chromosomal abnormalities have complex problems, often associated with developmental disability. Parents faced with this knowledge have to make difficult choices; some opt not to continue the pregnancy. Testing for chromosome problems involves an 'invasive' procedure (e.g. amniocentesis) which can sometimes cause a miscarriage. Major chromosomal abnormalities (e.g. Down's syndrome) can be detected using a technique called PCR (Polymerase Chain Reaction). Smaller and less common imbalances require the baby's cells to be grown and examined. This procedure (karyotyping) is slow, labour intensive and only detects large imbalances that can be seen down the microscope. Array comparative genomic hybridisation (aCGH) is a new molecular test that can rapidly detect smaller (sub-microscopic) imbalances. When used in children with undiagnosed developmental disability it has detected imbalances (not detected by karyotyping) in 10% of cases. There is very little experience of using aCGH on fetal samples but small studies suggest it may detect 5-10% more imbalances than karyotyping. However, performing and interpreting array CGH is complex as not all imbalances cause problems - some are inherited from a parent and others appear not to have any adverse effect, so more tests are needed to understand the significance of a newly detected imbalance. We now know that the baby’s genetic material (DNA) is present in the mother’s blood and research has shown that this DNA can be used to diagnose Down’s syndrome. This means that we may be able to detect babies with this condition non-invasively by taking a sample of the mother’s blood, thereby avoiding the miscarriage risk associated with invasive testing (NIPD). This study will recruit 1500 fetuses being karyotyped because of an abnormality detected on a scan. NIPD will be performed using the mother’s blood sample. Arrays will be performed on villi and amniotic fluid cells in 6 genetics laboratories using agreed guidelines. In addition to the standard karyotype information, clinicians/parents will be informed of imbalances detected by aCGH where the significance is known (based on similar cases reported in the medical literature). We need costs for the arrays and the scientists to perform them. NHS costs are requested for midwives to recruit parents. In addition, we will find out what parents, health professionals and commissioners think of the new technology. We will make recommendations as to whether array CGH should replace fetal karyotyping.