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Syndrome’s genetic cause identified

A new intellectual disability syndrome has been described in patients. Using a mouse with remarkably similar characteristics, researchers now reveal how mutations in the β-catenin gene could cause it.

β-catenin and the brain: MRI brain scans for a normal mouse (left) and the batface mutant (right)

Our Neurobehavioural Genetics group, led by Patrick Nolan, has been working closely with other institutions in Italy and the Netherlands to document the clinical features of four patients with a new intellectual disability syndrome, all of which have dominant mutations in the β-catenin gene. A mouse identified with a similar phenotype and a mutation in the same gene has been used to investigate the underlying cause. This genetic model provides a valuable new tool to study β-catenin’s role in behaviour and cognition, and will allow us to understand and treat intellectual disability and other cognitive disorders.

The major feature of the syndrome was intellectual disability, which ranged from mild to severe, with autism spectrum disorder. In childhood, the patients had muscle weakness, with hypertonia and progressive spasticity in their legs. This was associated with development of unusual craniofacial features, with a small head (microcephaly) and an underdeveloped corpus callosum (hypoplasia). All had mutations in the β-catenin gene, to which these characteristic phenotypes were attributed.

β-catenin has a dual function, with crucial roles in both Wnt signalling and cell adhesion. It achieves the latter of these by interacting with cadherins on the cell membrane, forming a link to the actin cytoskeleton. This β-catenin/cadherin interaction is needed for synapses, the main form of communication within brain networks, to function. It therefore follows that mutations which prevent β-catenin from functioning can lead to behavioural and cognitive deficits. Using high-throughput genomics approaches, different groups in The Netherlands and US have implicated β-catenin in both autism spectrum disorder and intellectual disability.

Using the ENU mutagenesis screen at MRC Harwell, researchers in the Neurobehavioural Genetics group identified a mouse line with an inherited mutation in β-catenin, which they discovered to be a substitution of threonine 653 by lysine. This mutation significantly reduced β-catenin’s ability to interact with cadherins. It shared many of the same phenotypes observed in the patients, including craniofacial and brain abnormalities, and was named ‘batface’ (Bfc), due to its characteristic broad facial features.

Batface has and an abnormally rounded brain shape, enlarged at the sides and smaller at the front and back, and MRI scans revealed a striking deficit in corpus callosum connections between the two hemispheres. As might be expected from this, batface mice had substantial behavioural and cognitive deficits, with particular difficulty in tests measuring decision-making, learning and memory.

This research has revealed the vital role β-catenin plays in cognition, and highlights the devastating consequences of mutations that disrupt its function. It is hoped that this mouse model will enable this syndrome to be studied in more detail, and will ultimately lead to new treatments for patients.

Tucci et al. (2014) Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features. J Clin Invest. 124:1468-82.


Oxfordshire science festival

We were at Oxfordshire Science Festival in Bonn Square on Saturday 8 March to talk about our research into neurodegenerative disease and teach kids about the brain with Air Dough and pipe-cleaners.

This year’s Oxford Science Festival was held under beautiful blue skies. Families flocked to Bon Square to browse the stalls, enjoy the sunshine and discover more about the exciting science going on at organisations in their local area.

Our stall this year was all about the diseased and healthy brain. We had information sheets laid out so that people could see the difference between the brain of someone with Alzheimer’s disease and a healthy brain, find out about amyloid plaques and neurofibrillary tangles, and ask us questions about their own experiences with relatives and friends.

For the children, we had a range of hands-on activities to teach them about the brain. There were two tables, each with different activities. On one, we had a model of the brain as it sits inside the skull, which you could take apart to see all the different components and how they fitted together. There was also a multi-coloured map of the cortex, showing the different brain areas and what thoughts and actions each one is responsible for, which the children used to make their own brain map model out of Air Dough. Alternatively, they could choose to draw the brain map on an MRC T-shirt, and we had some beautifully labelled diagrams. One girl even started a trend by adding ‘I love my brain!’ underneath hers.

On the other table, the children learnt all about the nerve cells that make up the brain. By twisting pipe-cleaners into neurons, complete with a cell body, dendrites, an axon and the myelin sheath, they found out what a neuron is made of and what each part does. We had a diagram to explain how neurons connect together to make a complex web in the brain, and how this allows us to think, feel pain, have emotions and remember. When it was time to go, they took their creations home with them.

In addition to studying Alzheimer’s disease, we also conduct research into the genes involved in other neurodegenerative disorders, including frontotemporal dementia, Huntington’s disease and amyotrophic lateral sclerosis. By studying the effects of these genes, we can work out what causes cells in the nerves and brain to die. And the more we know about what causes the disease, the closer we get to developing new treatments for patients.

The festival was a wonderful opportunity to connect with the public, and we greatly enjoyed the day. There was a lot of interest in our research, with plenty of questions and some touching stories, and it reminded us why our work is needed and who we are doing it for.

We will also be at Market Square in Abingdon on Saturday 22 March, so please come along and see us!


Life as an apprentice at Harwell

This week is National Apprenticeship Week 2014, so we decided to take little time to reflect on our own apprenticeships here at MRC Harwell, and our apprentices’ thoughts on their experience.

This year National Apprenticeship Week started on 3 March. The idea behind it is to raise the profile of apprenticeships amongst individuals, employers, teachers, parents and the media, and this year is marks the seventh year it has been running. We believe that apprenticeships play a vital role in getting young people into work and can be hugely advantageous to both the apprentice and the employer.

Here at MRC Harwell, we have apprenticeships in both the Estates and Engineering division and in science at the Mary Lyon Centre. Our first apprentice, pictured above with his colleagues from Estates and Engineering, was awarded his indenture last year. Since then, our apprenticeship scheme has grown and we have welcomed many more talented young people.

Joshua Cox, an apprentice working in the histology group, is now coming to the end of his time here. Looking back, he reflects on his experience. ”I have thoroughly enjoyed the apprenticeship. It’s great to learn in a practical manner, and my time here has been excellent. Highly skillful and knowledgeable staff have made the learning process fun and interesting.”


Careers fair at Magdalen College School

Our stand at Magdalen College School and Headington School careers fair on Tuesday 4 March was a great success, with huge interest and masses of questions from students about career opportunities at MRC Harwell.

Choosing your career path can be a daunting prospect. With so many possible careers out there, students must decide which subjects to take to reach their dream job. Yet few people know exactly what they want to do from an early age, and for most there comes a time when they must find out what options there are and decide which they will pursue.

We spent an evening at a careers fair to offer guidance and inspiration to pupils of Headington School and Magdalen College School in Oxford to help them find their way through the maze of careers.

Our stall was run by Dr Nanda Rodrigues, Head of Scientific Business and Administration. She has worked as a research assistant, studied as a postdoctoral researcher at Oxford University and has an MBA. As part of her current role she also organises outreach events. This meant she was perfectly placed to answer questions and offer advice, based on her own experiences, for almost every career we offer at Harwell.

The stall was decorated with our MRC banner and a tablecloth depicting our spread of possible careers. We wanted to not just make students aware of careers in science such as a technician, postdoctoral researcher and senior scientist, but also others they might not previously have considered.

We spoke about our team of bioinformaticians and roles in business, administration and communications. In addition, we mentioned our vibrant community of PhD students and range of apprenticeships.

The stand was very popular, with a continual stream of students coming to find out more about the opportunities we offer and discuss what they need to follow their chosen career, and we had very positive feedback from the schools. It was a rewarding experience that we hope helped the students to make one of the most important decisions of their life.


Mary Lyon chosen as a ‘Heroine of Science’

Sixth form students from The Abbey School in Reading have chosen to enter Mary Lyon as their ‘Heroine of Science’ for a National Science and Engineering Week competition at the University of Reading. On Tuesday 18 February, they visited Harwell to find out more about her life here and the incredible discovery she made.

Mary Lyon was a truly inspirational scientist. At a time when very few women worked in science, she graduated from Cambridge University in 1946 and went on to study for a PhD in genetics. She specialised in genetics, a route which led her to MRC Harwell, then a centre for research into the genetic effects of radiation. During her time at Harwell, she developed her theory of X-chromosome inactivation, also known as Lyonization, and in 1961 published it in Nature.

Her discovery led to great advances in our understanding of X-linked inherited diseases such as haemophilia, Duchenne muscular dystrophy, fragile X syndrome and certain cancers. In recognition of her achievement, the Mary Lyon Centre at Harwell is named after her, she is a Fellow of the Royal Society and in 1984 she received their Royal Medal, and she has been awarded the Pearl Meister Greengard Prize, the March of Dimes Prize and the Wolf Prize in Medicine. Despite this, her name is not widely known.

Emily Wilson, Stephanie Franklin and Catherine Waldron first became interested in Mary Lyon after reading about her in a book. Driven by a shared interest in genetics, they were inspired by her work and decided to enter her as their Heroine of Science for a competition run by the University of Reading. For this, they must give a short presentation on a female scientist of particular note. When they discovered Mary used to work at Harwell they got in touch to ask if they could visit.

“The three of us read the book ‘The Epigenetics Revolution’, and there’s a whole chapter on Mary Lyon and X-inactivation,” said Stephanie. “I think it just caught our imaginations and inspired us to do a bit more research into the woman behind the theories.”

One of the clearest examples of X-inactivation Mary used was the genetics of tortoiseshell cats. Like humans, female cats generally have two X-chromosomes (XX), whereas males only have one (XY). Two variants of a gene on the X-chromosome decide whether or not a cat will have a ginger coat. Males either have an entirely ginger or non-ginger coloured coat, as they only have one X-chromosome and one version of the gene, but for tortoiseshell females it is more complicated. One X-chromosome in each cell is randomly inactivated early in development, so the active gene is different in different groups of cells. These then give rise to their characteristic patches of ginger and non-ginger coat.

The girls were given a full tour of MRC Harwell, covering both the Mammalian Genetics Unit and the Mary Lyon Centre. In the library they delved into the archives to gain a deeper insight into her life and the events that led up to her discovery. They found the original boards that she used to present her theory of X-inactivation and looked through photographs taken when she was young. One of the girls pulled out a group photo with Mary that we later deduced must have been taken at the Royal Society. The gender imbalance could not have been starker – every other person in the photo was male.

To conclude their visit, they had lunch with Peter Glenister, who used to work with Mary at Harwell. They were eager to find out what she was like as a person and he was happy to recall his memories. He described her as an inspirational lady who was always one step ahead. Even though she is now retired, she maintains a strong interest in the science and still reads the current scientific literature.

Remembering how she wanted the first computer at Harwell in order to map chromosome bands, Peter said, “Mary Lyon made my career really, and she was full of foresight. We all know what a personal computer is today, but she had the first personal computer here. She had the foresight to see things like that, foresaw the way things would go.”

We are proud that the girls have chosen Mary Lyon as their heroine and wish them the best of luck in the competition. We share their hope that this talk will help Mary to receive the recognition she deserves. “We wanted to choose someone that wasn’t well known, someone that deserved more recognition and to be better known,” said Stephanie. “Her work is still having an impact now and there’s so many applications of it. We’re just hoping to make people more aware of that.”


Scout group visits MRC Harwell

We welcomed the 4th King Alfred scout group from Wantage on Monday 3 February for an evening of hands-on activities and challenging questions.

In our specially set up teaching lab, the scouts each got to have a go at doing their own experiment. They experienced what it is like to dress up as a scientist, and were kitted out from head-to-toe in lab coats, gloves and safety glasses. Each scout was given a strawberry in a plastic bag, washing up liquid and ethanol, and taught how to use these basic household items to extract DNA. They mashed up the strawberry, mixed it with the washing up liquid, added the ethanol, and fished out a strange white goo. This peculiar substance, they were told, was strawberry DNA, and each got to put theirs in a tube and take it home to show their parents. As they hung up their lab coats and walked out the lab, they chatted excitedly about how they would try it again at home with kiwi fruit or bananas. One boy even thought about using his Dad’s favourite rum.

Next stop was the conference room, where laptops were laid out on the table waiting for them. Here they learnt about the enormous quantities of data generated from experiments at MRC Harwell and the computational tools we use to make sense of it all. Each scout got to play around with a 3D model of a protein on their screen, twisting it around and stripping away the outer layers to delve into its inner intricacies. There were questions about the type of mice used, how experiments here are actually done and the collaborative effort needed for such a massive undertaking.

In our engagement room, one child was handed a plastic bunch of blackberries. Was it heavy? No, they answered. What animal’s brain would weigh the same amount? The same question was put to the group for a bunch of bananas, a pineapple and an enormous melon, and a pattern emerged – the bigger the brain in proportion to the rest of animal, the more intelligent it was.

The group then turned to another part of the room, where they found a row of shopping baskets filled with all kinds of toy food, from chocolate muffins to packets of cereal, and each scout picked out what they thought was a healthy breakfast. After they had chosen their food, everyone gathered together to show what they had on their plates and explain why they thought it was healthy. The scouts also learnt about the importance of exercise, using a stethoscope to listen to their heartbeat. When standing still they struggled to hear it, but after jogging on the spot for 30 seconds, some said they could even hear it without the stethoscope!

For their final task, the scouts made a cell. They were given a choice of colours of Air Dough, which is similar to Plasticine but dries hard like clay. Our plastic 3D model of a cell was brought out as an example and each of the inner parts identified, including the nucleus, which they learnt holds the DNA. They moulded everything from mitochondria to the endoplasmic reticulum in brightly coloured brilliance, and at the end of the day they took their creations home.

Sex reversal defect explained

Expression of the gene Map3k4 has rescued testes development in mice with a type of sex reversal, demonstrating the important role this gene plays in directing the development of the gonads.

Switching sex: Gonads of female (far left) and male (second from left) mice, compared to a sex reversed male (second from right) and a sex reversed male with Map3k4 expression (far right)

Sex reversal can occur in both humans and mice. The most common human condition, 46, XY gonadal dysgenesis, is a disorder of sexual development (DSD) that in chromosomal males can result in female genitalia and a complete absence of testes. Similarly, XY mice with a deletion on chromosome 17, called hairpin-tail (Thp), develop ovotestes or ovaries instead of testes – a phenomenon known as T-associated sex reversal (Tas).

MAPK signalling, consisting of a network of enzymes that can activate or inhibit different cellular processes, has previously been implicated in human sex determination and DSD. In mice, MAPK signalling is known to be required for the development of testes - embryos lacking one enzyme, MAP3K4, are sex reversed. However, although it was known that Map3k4 resides within the Thp deletion, it was not clear whether reduced Map3k4 expression causes T-associated sex reversal.

To test this, the Molecular Genetics of Sexual Development group, led by Andy Greenfield, used bacterial artificial chromosomes to add extra copies of Map3k4 to mice with the Thp deletion. This resulted in the re-establishment of gene expression patterns that had been disrupted in the Thp deletion mice. They discovered that this eliminated the male-to-female sex reversal. Mice treated showed no signs of the disorder, and developed testes rather than ovotestes or ovaries.

To investigate exactly how the expression of Map3k4 brought about this change, they studied the expression of Sry, a key gene on the Y chromosome that controls the development of the embryonic gonads into testes. Sry expression in the gonads was low in the mice with T-associated sex reversal but was increased due to the boost in Map3k4 expression. They therefore concluded that Map3k4 drives the development of male sex organs by regulating the expression of Sry.

Overall, this research has revealed that Map3k4 is a key player in determining sex in mice, and that its expression is essential for correct sexual development. Since MAPK signalling has been associated with the human condition 46,XY gonadal dysgenesis, this mouse model could also be crucial for understanding sex determination and DSDs in people.

"We were part of a study back in 2010 that established the existence of mutations in a gene called MAP3K1 in humans with a condition known as 46,XY gonadal dysgenesis - the development of XY individuals as females,” explained Andy Greenfield. “To understand the basis of this sex reversal, we need mice that model this phenomenon.

"Tas mice, which sex reverse due to a chromosomal deletion, are an excellent model and our work with Map3k4 shows how gene dosage can be important in controlling testis determination in mice and humans. We can now study the causes of sex reversal in more detail and hopefully explain other examples of XY sex reversal and related disorders in humans."

Warr, N. et al. (2014) Transgenic expression of Map3k4 rescues T-associated sex reversal (Tas) in mice. Human Molecular Genetics.


New male Pill on way in DNA breakthrough

New male Pill on way in DNA breakthrough (Scotsman, p17)

A new male contraceptive pill could be created after scientists in Scotland discovered a key reproductive gene. Experts are also hopeful the breakthrough could also lead to new treatments for male infertility. Researchers from Edinburgh University have found a key gene essential for sperm development. They hope the study will lead to the creation of new methods of male contraceptives that do not disrupt the production of hormones, something which often creates side effects including mood swings and acne. The researchers have discovered the gene, Katnal1, is critical to enable sperm to mature in the testes. They now hope to find ways to regulate the gene to prevent sperm from maturing, making them ineffective.

Dr Lee Smith, reader in genetic endocrinology at the Medical Research Council Centre for Reproductive Health at the university, said: “The identification of a gene that controls sperm production in the way Katnal1 does is unique and a significant step forward in our understanding. If we can find a way to target this gene in men, we could potentially develop a male non-hormonal contraceptive.”

The research could also help in finding treatments for cases of male infertility, when malfunction of the Katnal1 gene hampers sperm development. The researchers found that Katnal1 was needed to regulate a structure, known as microtubules, which forms part of the cells that support and provide nutrients to developing sperm. The breakdown and rebuilding of these microtubules, enable the sperm cells to mature and Katnal1 acts as the essential controller of this process. The study, which was funded by the Medical Research Council, also revealed the possibility of introducing a DNA sequence that permanently blocked Katnal1 as a method of permanent sterility, which the team have dubbed “genetic vasectomy”. Also reported in The Herald (p3) and the Independent (p13), and BBC News Online

MRC media release – Potential new treatments for a common childhood hearing disorder

Scientists from the Medical Research Council's Mammalian Genetics Unit have identified a potential new treatment for 'glue ear' a common inflammatory condition in children that can cause temporary, but often prolongued, hearing loss.

The new study, published today in the journal PLoS Genetics, shows that several existing drugs currently used in cancer treatment, also relieve the symptoms of persistent ear inflammation in mice.

The research could eventually lead to an inexpensive, easy-to-apply localised treatment for glue ear, which could eliminate the need for children to undergo surgery to fit tiny ventilation tubes (known as grommets) into the ear.

Professor Steve Brown, Director of the Mammalian Genetics Unit who led the research, said:

"We found that one of the key factors in developing glue ear is a lack of oxygen reaching the middle ear. This lack of oxygen, known as hypoxia, appears to prevent the inflammation in the middle ear resolving, allowing fluid to build up, which can impair hearing."

"By using existing drugs that tackle the root causes of hypoxia, we have been able to significantly reduce hearing loss and the build up of fluid in the middle ear of our mouse models. Furthermore, the fact that these drugs are already on the market means that the time and cost needed to develop them into a new treatment for glue ear could be dramatically reduced."

"The Medical Research Council is constantly striving to improve our understanding of the link between genetics and disease. By using mouse models of a human disease – like glue ear – we can gain a valuable insight into the disease process, which will eventually lead to better-targeted new treatments."

Glue ear is the common term for the medical condition otitis media with effusion. It occurs when the space behind the ear drum, called the middle ear, becomes inflamed and fills with fluid. This fluid dampens the sound waves entering the ear leading to varying degrees of hearing loss.

It is estimated that 90 per cent of children in England will have had at least one episode of middle ear infection by the age of five. Most children recover quickly, but some will go on to experience repeated bouts and a number will develop a chronic condition, where inflammation continues, leading to the middle ear filling with a thick glue-like fluid. The associated hearing loss can cause both social and developmental delays in the child, including delayed language acquisition.

The only reliable treatment currently available for recurrent and chronic glue ear is the surgical insertion of grommets into the eardrum to improve ventilation. Grommet insertions are the most common operation in the UK, with around 30,000 procedures carried out each year. However long-term success is variable and around one in four children will need further operations.

Scientists are therefore keen to develop new treatments that are more effective and less invasive for the child. The authors of this study aim to repurpose the existing drugs (known as VEGF inhibitors) into a treatment that can be delivered directly into the ear at the site of inflammation, which should help to eliminate any potential side-effects.

More work is needed to replicate the study in humans to make sure that the underlying disease process is the same as the mouse model, but the authors are optimistic that a new treatment could reach early-stage clinical trials in around five years.

Dr Ralph Holme, Head of Biomedical Research at Action on Hearing Loss, added:

"Otitis media with effusion, more commonly known as glue ear, is a common cause of hearing loss amongst children and can affect language development and result in children falling behind at school. The research published today is an important step towards an effective pharmacological treatment for this common and distressing condition."

The research was carried out by the MRC Mammalian Genetics Unit and the Mary Lyon Centre at Harwell, and the University of Oxford.


Library of gene function will speed up disease research

An international project to create one of the largest libraries of mammalian genetic function data is to be launched on 29th September 2011.

The International Mouse Phenotyping Consortium (IMPC) is building a library of mammalian gene function which will describe the function of every gene in the mouse genome. Around 99 per cent of the genes in a mouse have an equivalent gene in humans. By understanding the function of all the genes within the mouse, scientists can improve their understanding of the role that genes play in human diseases such as heart disease and diabetes.

The IMPC programme will allow researchers from across the world to easily access all of the resources and information created by the programme on `knockout mice` - that is, mice in which scientists have inactivated (or `knocked out`) a gene in order to discover what that gene does. This will substantially shorten the time between basic research and clinical application. Dr Mark Moore, IMPC Executive Director, explains: "We want to characterise each line of mice broadly with no assumptions about what the gene may be doing."

"If you think of the function of a gene as a needle in a haystack, we`re removing the haystack so scientists can see what the needle does," he added.

The IMPC is a worldwide consortium comprising fifteen research institutions along with national funders from six countries, including the Medical Research Council (MRC) Harwell (UK), the National Institutes of Health (US), the Wellcome Trust (UK), the Wellcome Trust Sanger Institute and EMBL-European Bioinformatics Institute in Hinxton (UK), Helmholtz Zentrum München, German Mouse Clinic (Germany), Toronto Centre for Phenogenomics (Canada), Institute Clinique de la Souris (France), Australian Phenomics Network (Australia), RIKEN BioResource Centre (Japan), CNR Monterotondo (Italy), Baylor College of Medicine (US), University of California Davis (US), Charles River Laboratories (US), Children`s Hospital Oakland Research Institute (US), the Jackson Laboratory (US), Genome Canada (Canada), MARC Nanjing University (China) and Canadian Institutes of Health Research (Canada). This strong international partnership hopes to increase its membership as the programme moves forward.

"Our drive is to understand the role of genes in disease and use that understanding to improve healthcare," explains Dr Bill Skarnes, Senior Investigator at the Wellcome Trust Sanger Institute. "The cells and DNA resources we have developed for IMPC have already proved their value in identifying genes involved in a form of anaemia. The integrated resources delivered by IMPC will make a real difference to researchers` work around the world."

Funding has been awarded to members of the consortium by a number of national funding agencies. Recently, several members of the consortium have been awarded US $110m over five years by the NIH to work on the project; which includes the Knockout Mouse Phenotyping Project 2 (KOMP2) and MPI2. The first phase of this ten-year project will knock out 5000 mouse genes and describe their physical characteristics or phenotypes.

Each mutant will pass through a series of examinations similar to the examinations patients might experience at a doctor`s surgery or in hospital to diagnose their condition. All members of the IMPC will use standard agreed procedures to perform the biological investigations and the data will be deposited in a single international database. The set of tests is designed to give information on human disease, such as heart disease, diabetes, and deafness, and the results will determine if that gene has a part to play in those diseases. The mice and the data generated from them will be freely available to the scientific community.

Dr Francis Collins, Director of the NIH, says: "The addition of detailed clinical information for each knockout mouse line will be a boon to disease researchers who want to determine the function of genes and improve mouse models of human disease."

Professor Steve Brown, Director of MRC Harwell and Chair of the IMPC Steering Committee says: "The launch of the IMPC represents an outstanding example of international cooperation in the biomedical sciences. IMPC is an unprecedented and unique international biological research endeavor that brings together diverse expertise and facilities to tackle the enormous challenges of understanding the relationship between gene and disease. This latest funding boost from NIH along with the funding available from other funding agencies means the first phase of the project is on track."

Professor Martin Hrabé de Angelis of Helmholtz Zentrum München and coordinator of Infrafrontier, a world class pan European research consortium for systemic phenotyping and archiving of mouse models, says: "This is an outstanding and unique opportunity to leverage existing know how and infrastructures in different continents by running a so far unmatched global programme to unravel gene functions of human diseases."

Data generated by the IMPC will be used by pharmaceutical and biotechnology companies to speed-up the development pipeline of new drugs. Dr Tom Weaver, Director of the MRC Mary Lyon Centre which is one of the IMPC production and phenotyping centres, explains: "There are literally hundreds if not thousands of drug targets that have yet to be discovered. The application of mouse genetics in combination with phenotypic analysis is recognized as an essential method for identifying and validating drug targets and drugable pathways. They will serve as tools to understand the mechanisms of action of drugs in vivo, and efficacy testing prior to expensive clinical trials."

Underpinning the IMPC project has been a lengthy period of planning and technical preparations. A fundamental component of this has been the planning for a data coordination centre (DCC) which will allow unrestricted public access to IMPC data. Dr Ann-Marie Mallon, Head of Informatics at MRC Harwell explained "We are committed to make data from IMPC public in an accurate, timely, and intuitive manner to ensure any institution or researcher around the world can access this data and the genetically modified mice".

Dr Paul Flicek, of EMBL-EBI, added: "The open resources created by IMPC will be integrated with many other molecular databases at EMBL-EBI and elsewhere, and benefit from advanced search functionality. This will ensure that researchers can make use of detailed data and high-level summaries of mouse phenotypes and other relevant biological information - for example human disease associations - well into the future."

The IMPC is building on the successful and ground-breaking EUMODIC project (funded by the European Commission under grant LSHG-CT-2006-037188) which developed the SOPs and IT systems needed to store the vast amounts of data generated and piloted the production and phenotyping of the mice. IMPC is therefore building upon years of planning and technical preparation.

NIH to make a mightier mouse resource for understanding disease ($110 million funding announced), September 29, 2011 News Release - National Institutes of Health (NHI).


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