OUR VISION

Our vision is to achieve extraordinary improvements in human and animal health. In pursuit of this, we support the brightest minds in biomedical research and the medical humanities.

We focus on three key areas of activity, reaching across five major research challenges.

FOCUS AREAS

Our funding focuses on supporting outstanding researchers, accelerating the application of research and exploring medicine in historical and cultural contexts.

Outstanding researchers

We believe passionately that breakthroughs emerge when the most talented researchers are given the resources and freedom they need to pursue their goals.

Application of research

We are committed to maximising the application of research to improve health by focusing on new product development and the uptake of patient-oriented research advances into clinical practice.

Medicine in culture

We strive to embed biomedical science in the historical and cultural landscape, so that it is valued and there is mutual trust between researchers and the wider public.

RESEARCH CHALLENGES

Our five major challenges address some of the most pressing and fundamental problems that confront human and animal health.

To tackle these challenges we provide support within the UK and abroad for biological, clinical and translational research, public engagement activities and an exploration of the historical, cultural and ethical issues.

Maximising the health benefits of genetics and genomics

We fund a wide array of research into how genes affect health and disease, and work to ensure that this knowledge lead to new ways to diagnose, treat and prevent illness. Further information and examples

Understanding the brain

We support research to improve understanding of how the brain functions and to find improved approaches for treating brain and mental health disorders. Further information and examples

Combating infectious disease

Finding new ways to prevent and treat the bacterial,viral and parasitic diseases that kill millions of people worldwide every year. Further information and examples

Investigating development, ageing and chronic disease

We aim to develop an integrated understanding of how the body develops, functions and ages, and of the factors that contribute to the onset and development of chronic disease. Further information and examples

Connecting environment, nutrition and health

Global health is under serious threat from the interlinked issues of access to nutrition, food security and climate change. We foster a multidisciplinary approach to address these problems.

FUNDINGS TO BIOMEDICAL SCIENCE

Our funding supports the brightest minds in biomedical research and the medical humanities, with the aim of improving human and animal health. We support research into all aspects of biomedical science: from molecules and cells vital to life, through the spread of diseases or the vectors of disease across the globe, to clinical and public health research to improve the quality of healthcare.

Research can be based in the laboratory, the clinic or the field, and may involve experimental or theoretical approaches.

We do not just fund scientists - through our biomedical science grants we support undergraduate and doctoral students, clinicians, dentists and veterinarians. We fund the best researchers with the most innovative and exciting ideas, and we devote a significant proportion of our funding to support those working overseas, in the form of personal and research support, collaborations and support for symposia, conferences and workshops.

About biomedical science

We support molecular, cellular and structural biology,as well as clinical, physiological, psychological,epidemiological and public health research.

Our funding schemes

· Investigator Awards

· Fellowships

· Strategic awards and other initiatives

· PhD funding and undergraduate opportunities

Investigator Awards

These awards build on our strategic goal of supporting the brightest researchers with the best ideas, and extend our successful fellowships funding model to researchers in established academic posts(that is those who have permanent, open-ended or long-term rolling contracts of employment salaried by their university or research institution).

o New Investigator Awards

—Support world-class researchers who are no more than five years from appointment to their first academic position, but who can already show that they have the ability to innovate and drive advances in their field of study. The Awards provide support that is flexible and at a level and length sufficient to enable exceptional researchers to address the most important questions about health and disease.

o Senior Investigator Awards

—Support exceptional, world-class researchers, who hold an established academic position and have a compelling long-term vision for their research. The Awards provide support that is flexible and at a level and length sufficient to enable exceptional researchers to address the most important questions about health and disease.

Fellowships

Opportunities for support are available for scientists at all levels who are working on research projects relevant to the biomedical sciences. We also support lowand middle-income country scientists working in public health or tropical medicine. Research projects can be based in the laboratory, the clinic or the field and may involve experimental or theoretical approaches.

Where appropriate, applications are encouraged from candidates trained in disciplines outside the biomedical sciences who are applying their expertise to biomedical problems.

Basic biomedical fellowships:

Support for postdoctoral researchers in basic biomedical science at each stage of their career.

o Sir Henry Wellcome Postdoctoral Fellowships

—Provide support for the most promising newly qualified postdoctoral researchers.

o Research Career Development Fellowships in Basic Biomedical Science

—Provide an opportunity for postdoctoral scientists to become independent research scientists and to undertake research of high quality.

o Senior Research Fellowships in Basic Biomedical Science

—Provide support for exceptional individuals who can demonstrate their ability to carry out independent research.

o Career Re-entry Fellowships

—Provide postdoctoral scientists who have had a recent break of at least two years with the opportunity to return to high-quality research, with the potential for refresher or further training.

Clinical fellowships:

Support for clinicians at each stage of their careers.These schemes are open to individuals qualified in medicine, dentistry, veterinary science or clinical psychology wishing to conduct research in their field.

o Research Training Fellowships

—Provide support for medical, dental, veterinary or clinical psychology graduates who have little or no research training, but who wish to develop a long-term career in academic medicine.

o Postdoctoral Training Fellowship for MB/PhD Graduates

—Provides support for new qualified MB/PhD graduates to make an early start in developing their independent research careers.

o Intermediate Clinical Fellowships

—Provide support for outstanding medical, dental, veterinary or clinical psychology graduates to continue research interests at postdoctoral level and develop towards independence.

o Senior Research Fellowships in Clinical Science

—Provide support for clinical investigators to further develop their research potential and to establish themselves as leading investigators in clinical academic medicine.

International fellowships:

o International Senior Research Fellowships

—Provide support for outstanding researchers, either medically qualified or science graduates, who wish to establish a research career in an academic institution within their chosen country.

o Wellcome Trust-Massachusetts Institute of Technology (MIT) Postdoctoral Fellowships

—Offers opportunities for postdoctoral scientists to undertake research at the interfaces between biology/medicine and mathematics, engineering,computer, physical or chemical sciences, firstly at MIT and then at a UK institution.

Strategic awards and other initiatives

Strategic Awards are highly flexible and provide support for initiatives that might otherwise be unavailable through our other funding schemes. They give us a mechanism that is both versatile and responsive to significant funding opportunities. In particular, these Awards support research to address the challenges outlined in the Trust's Strategic Plan 2010-20.

Preliminary applications for individual Strategic Awards may be submitted at any time and are assessed on a rolling basis.

From time to time we also use targeted calls for initiatives to develop and support strategically important topics within and across our five challenges.

Strategic Awards provide flexible forms of support to facilitate research and/or training that is not possible under existing schemes. The aim is to add value to excellent research groups.

Current themed initiatives:

o Biomedical resource grants

—Provide support for researchers wishing to establish or maintain biomedical resources (including databases and collections) for the benefit of the wider scientific community.

o Multi-user equipment grants

—Provide support for multi-user items of equipment,including equipment required to create a central resource for a number of disparate scientific programmes.

o Global health trials scheme

—Support for late-stage trials of interventions that

will help improve health in low- and middle- income

countries, by addressing the major causes of

mortality and morbidity.

o Human Heredity and Health in Africa

—Provide support for the creation and development of the necessary expertise and infrastructure in Africa and establish pan-African research networks.

o E-Health Informatics Research Centres (E-HIRCs)

—Provide support for new centres of excellence in health informatics (e-health) research, with the aim of conducting cutting edge research and building capacity in the area.

Other schemes:

o Wellcome Trust and Howard Hughes Medical Institute Exchange Programme

—Promotes international collaborations among scientists funded by the Trust and the Howard Hughes Medical Institute.

o Starter grants for clinical lecturers

—Research-active clinical lecturers can apply for modest funding to cover the cost of consumables to enable them to gather data to strengthen applications for longer-term fellowships and funding.

PhD funding and undergraduate opportunities

We support the most promising students and clinicians with high-quality, well-funded, postgraduate research training, and provide promising undergraduates with hands-on research experience in the biomedical sciences.

PhD programmes and studentships:

o Clinical PhD Programmes

—Support the most promising medically qualified clinicians who wish to undertake rigorous research training.

o Four-year PhD Studentship Programmes

—Provide high-quality, well-funded, postgraduate research training over a four-year period.

o Joint Basic and Clinical PhD Studentship Programmes

—Support the most promising basic or medically qualified clinicians who wish to undertake both rigorous basic and clinical science research training.

o Research Training Fellowships

—Provide support for medical, dental, veterinary or clinical psychology graduates who have little or no research training, but who wish to develop a long-term career in academic medicine.

o Integrated Training Fellowships for Veterinarians

—Provide support for veterinary graduates - normally with an intercalated degree and/or a demonstrable interest in research - who wish to develop a career in biomedical research by obtaining a laboratory-based PhD and clinical training.

o Translational Medicine and Therapeutics Programmes

—Four high-quality integrated research training programmes for clinicians in translational medicine and therapeutics.

o Wellcome Trust and NIH Four-year PhD Studentships

—Provide support for collaborative PhD training between laboratories in the UK/RoI and the NIH in Bethesda.

Undergraduate support:

o Biomedical Vacation Scholarships

—Provide promising undergraduates with hands-on experience of research for up to eight weeks during the summer vacation.

o iGEM Student Stipends

—The Wellcome Trust wishes to offer a number of student stipends to support the participation of UK teams in the Internationally Genetically Engineered Machine (iGEM) Competition.

o Student Elective Prizes

—Enable outstanding medical students to gain experience and training in biomedical research during their elective period.

Research opportunities

General eligibility

Please note that this information does not cover candidate eligibility for our fellowship schemes - please refer to specific fellowship schemes for details.

· Principal applicants

· Coapplicants

· Overseas applicants

· Retired workers

· Sponsors

· Organisations

· Overseas organisations

· Restrictions on intellectual property rights

· Additional information

Principal applicants:

Must be established researchers who are expected to apply from an eligible organisation, able to sign up to the Wellcome Trust's Grant Conditions and, should normally:

· hold an academic or research post (or equivalent)

· have at least five years' postdoctoral (or equivalent) research experience. Individuals who hold an established lectureship or a well-recognised fellowship (e.g. Royal Society University Research Fellowship) but who have less than five years' postdoctoral experience are also eligible. Other researchers with less than five years' experience should contact the relevant funding stream for further advice.

· be in receipt of salary funding for the duration of the grant requested or have at least one year's personal salary support at the proposed start date of the grant.

· Alternatively, applicants who are seeking their own salary support may apply as either the principal applicant or coapplicant depending on their level of input into the research. If this applies to you please contact the relevant funding stream for advice as you may be required to submit a CV and full publication list.

Coapplicants:

As above for principal applicants. In addition, postdoctoral research assistants, whether seeking their own salary as part of the grant proposal, funded by the Wellcome Trust on another grant or funded by another agency, are eligible for coapplicant status if they make a significant contribution to a research proposal and have agreement from their funding agency.

Research assistants seeking coapplicant status:

See above. In addition, research assistants already funded on a Wellcome Trust grant must inform the Wellcome Trust before submitting an application where they are named as a coapplicant, indicating how much time they expect to spend on the new project.

Research assistants funded by another agency must provide written confirmation to the Wellcome Trust from their funding agency that the amount of time they propose to spend on the project is acceptable. Contact us to discuss your situation with a member of staff in the appropriate funding stream before applying.

Overseas applicants:

Overseas applicants should fulfil the eligibility criteria for principal applicants above. Researchers from low- or middle-income countries who have a track record of Wellcome Trust funding as a principal investigator, coapplicant or fellow may apply directly for certain types of support without a UK based collaborator.

Retired workers:

Retired workers may be eligible to apply for some schemes as an applicant or coapplicant, with the support of a sponsor. Potential applicants should contact the Trust for advice.

Sponsors:

As above for principal applicants. In addition,sponsors must be in a position to guarantee space and resources for the duration of the grant and hold a contract of employment that extends beyond the grant.

Organisations:

Eligible organisations are 'not for profit' research institutes that are able to sign up to the Wellcome Trust's Grant Conditions.

Non-university organisations in the UK/Republic of Ireland may be required to have reciprocal arrangements in place to allow staff at the Wellcome Trust Sanger Institute to apply for funding. Reciprocal arrangements are in place with the Medical Research Council (MRC), the Biotechnology and Biological Sciences Research Council (BBSRC),and Cancer Research UK (CRUK). Staff in their units and institutes are eligible to apply.

Overseas organizations:

The funding that the Trust provides overseas is largely focused on low- and middle-income countries. Normally, research organisations that are not for profit, able to sign up to the Trust's Grant Conditions and have a mission statement broadly in line with that of the Trust, are eligible to apply for support.

Restrictions on intellectual property rights(IPR)/publications:

If there are any restrictions on IPR or publications arising from your research, you must provide a written statement detailing these. Restrictions on intellectual property may affect your eligibility to apply to the Wellcome Trust. Contact the relevant funding stream for more information.

How to submit an application

· Preliminary applications

· Full applications

· Additional guidance

Preliminary applications:

Some schemes - mostly personal support schemes- require a preliminary application. The main purposes of preliminary applications are:

· to assess the eligibility of applicants and research proposals

· to check that applicants are applying for the most appropriate scheme.

The quality of the proposed research is not judged at this stage. If applicants are eligible to apply, they are invited to submit a full application.

Before submitting an application you should refer to the application information.

Written preliminary applications:

For other types of support that require a preliminary application, enquiries should be made either by email or in writing and may include:

· brief details of the proposed research (one A4 page maximum)

· a note of existing funding from all sources, including the source of the applicant's salary funding

· a brief CV

· a list of relevant publications

· an approximate costing

· for fellowship and studentship applications, a letter of support from an academic sponsor.

Refer to the relevant web page for each scheme for details on how to submit a preliminary application,as well as any additional information that may be required.

Preliminary applications and other written enquiries should be sent to the most relevant funding stream.

Full applications:

Submission of full applications via our eGrants application system, where a form is available, is mandatory. Most application forms for Biomedical Science and Medical Humanities schemes are available on the eGrants system; however, Word forms are still available for:

· Public Engagement grants

· Technology Transfer grants

· Applicants who have limited/unreliable access to the internet. Please email the eGrants service desk –egrants.support@wellcome.ac.uk - if this is the case.

Additional guidance:

General guidance for all applications (including fellowships):

· When received, an application will be subject to the Wellcome Trust's normal selection procedure and will be considered in competition with other similar type applications.

· If you submit a full application and either you are ineligible to be an applicant or the subject of your proposal does not fall within the Wellcome Trust's remit, the Wellcome Trust reserves the right not to process your application.

· The Wellcome Trust's willingness to consider the application in no way implies that support will be forthcoming.

· You are expected to inform the Wellcome Trust if you subsequently decide to submit this or a similar proposal to another funding body while this application is still being considered by the Wellcome Trust. Non-compliance may lead to refusal to consider the application. If applicants request funding for the same costs on more than one application to the Wellcome Trust at any one time, they must make this clear in their application.

· Additional data may be submitted up to two weeks before the date of the decision-making committee meeting; after this date, no extra information will be accepted.

· Depending on when you submit your application, it may take between four and six months to process. You should therefore allow at least six months between submission and the proposed starting date. However, certain awards are made once or twice a year. For the timescales and deadlines to be met for a specific scheme, please refer to the detailed information about that specific scheme.

· Abbreviations should not be used unless fully explained.

· If there are any ties on intellectual property rights or publications arising from the research you undertake, please contact the Wellcome Trust for advice. Restrictions on intellectual property may affect your eligibility to apply to the Wellcome Trust.

· A revised Concordat to Support the Career Development of Researchers was agreed in June 2008. The Wellcome Trust expects organisations that hold Wellcome Trust grants to adopt the principles of the revised Concordat for the management of their researchers.

General guidance for all fellowship applications:

· Fellowship applicants must not apply to more than one Wellcome Trust Fellowship scheme at any one time.

· Holders of Wellcome Trust fellowships must contact the Trust before submitting a full application for a grant on which they are a principal applicant or coapplicant.

· Each fellowship application also requires the support of the head of department in which the work will be carried out. In some applications,the head of department may also be the sponsor.

Biomedical science funded projects

Our funding supports individuals, collaborations and large-scale initiatives in the biomedical sciences.

Major initiatives Examples of the strategically important initiatives and projects we have funded in the biomedical sciences in the UK and internationally.

· African Institutions Initiative

· Avon Longitudinal Study of Parents and Children (ALSPAC)

· Cancer Genome Project

· Centres for Research in Clinical Tropical Medicine

· Clinical Research Facilities

· Diamond synchrotron

· Health research capacity in Kenya and Malawi

· Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory

· London Pain Consortium

· Major Overseas Programmes

· Millennium Seed Bank

· Neurodegenerative Diseases Initiative

· SNP Consortium and International HapMap

· Structural Genomics Consortium

· Wellcome Trust Case Control Consortium

· Wellcome Trust Centres

· Wellcome Trust Sanger Institute and the Wellcome Trust Genome Campus

· UK Biobank and the UK Biobank Ethics and Governance Council

· Unit for Drug Discovery Dundee

· 1000 Genomes Project

EXAMPLES OF OUR FUNDING RELATED TO NEUROLOGICAL SCIENCE

Understanding the brain

We fund a significant portfolio of neuroscience and mental health research - ranging from studies of molecular and cellular components to work on cognition and higher systems. We also have strong interests in applied clinical research on neurological and mental health disorders and support activities that explore historical, ethical, social and artistic perspectives on the mind and mental health.

We support multidisciplinary approaches that integrate molecular, physiological, behavioural and computational studies and embrace work that explores the ethical, social and philosophical questions raised by this research.

The following examples illustrate the work we have funded to develop a better understanding of the brain and mental health.

Integrating research efforts

At the Wellcome Trust Centre for Neuroimaging, clinicians and scientists study higher cognitive function to understand how thought and perception arise from brain activity, and how such processes break down in neurological and psychiatric disease. Other major integrated research programmes that we support include the London Pain Consortium, which facilitates broader approaches to the study of pain and trains the next generation of pain scientists, and the Neurodegenerative Diseases Initiative, which aims to develop better approaches for early diagnosis and therapeutic interventions.

Mental health disorders

We support a number of studies providing insights into the genetics of mental health disorders, such as the Bipolar Disorder Research Network. Our researchers have developed cognitive behavioural therapies to treat conditions such as eating disorders and post-traumatic stress disorder. We also support research looking at mental health problems in lowand middle-income countries. For example, the 10/66 Dementia Research Group revealed the true prevalence of dementia in these countries, and Vikram Patel is developing a sustainable healthcare programme for treating depression in southern India.

Translational research and innovation

To enhance the diagnosis and management of brain disorders, we have provided funding for the development and testing of a neonatal seizure detection system and for functional electrical impedance tomography of evoked responses, which will enable the brain imaging of more people than is currently possible. Our seeding drug discovery programme has funded a number of candidate therapeutics aimed at slowing or reversing the progress of diseases such as Alzheimer's disease,memory loss and dementia, spinal cord injury and brain tumours.

Public engagement and dialogue

To inform and engage the public in a better understanding of the brain and mental health, we have supported a number of short films and documentaries,including the award-winning films ‘The English Surgeon’ and ‘Love at First Sight’. We have supported the website mentalhealthcare.org.uk, which helps relatives and friends of people with mental health problems navigate through the many myths and misinformation about psychosis, and the ‘Troubled Minds’ series of animations, exploring issues affecting young people.

Neurodegenerative Diseases Initiative

A better understanding of the disease mechanisms underlying neurodegenerative disorders is urgently required if new treatments are to be developed. The Wellcome Trust and Medical Research Council Neurodegenerative Diseases Initiative was launched in 2008 to stimulate high-quality, collaborative and multidisciplinary research that would advance our understanding of the biological processes underpinning neurodegenerative diseases.

Three Strategic Awards funded: ￡17 million funding boost to UK neurodegenerative diseases research

In 2009, three new innovative and collaborative research programmes were supported. These multidisciplinary research programmes are focused on providing a better understanding of the causes of neurodegenerative diseases - Alzheimer's disease,frontotemporal dementia, Parkinson's disease and motor neurone disease - in a bid to develop better approaches for early diagnosis and therapeutic interventions for these diseases.

The multidisciplinary collaborations bring together leading academic research teams from around the UK,as well as leading international groups and pharmaceutical companies.

Mechanisms of neurotoxicity of amyloid aggregates One of three Strategic Awards funded under the WT/MRC Neurodegenerative Diseases Initiative is an innovative research programme aimed at discovering the molecular mechanisms that result in the death of brain cells in Alzheimer’s disease and related neurodegenerative disorders with accumulation of amyloid beta and/or tau and identifying novel therapeutics. To find out more about this collaboration visit the Cambridge Bristol Toronoto Hamburg Neurodegenerative Disease Consortium website.

The problem:

Alzheimer's disease and related disorders are increasingly common degenerative disorders of the brain that occur in mid-to-late adult life. They cause impairments in memory and intellectual function,and lead to death within 10-15 years of diagnosis.In the UK, 700 000 people suffer from dementia (in around 450 000 of cases this is caused by Alzheimer's disease) and this number will double to 1.4 million by 2037. These diseases cost the UK economy about ￡17 billion, which will rise to at least￡50bn by 2037.

Worldwide, 37m people are affected by these diseases - they are the fourth leading cause of death among adults in industrialised societies, and are becoming an increasingly significant healthcare problem in low- and middle-income countries.

Although we know that several genes and environmental effects can cause Alzheimer’s disease, we do not know why or how they lead to the death of nerve cells in the brain.

The paucity of knowledge about the molecular mechanics of these diseases has hampered the development of sensitive and accurate tests and effective treatments.

The questions:

The accumulation and aggregation of two proteins in the brain - amyloid beta and tau - is a characteristic feature of Alzheimer's disease, while the accumulation of tau alone is characteristic of a related disorder called frontotemporal lobar degeneration-tau type. Mutations or variants in the amyloid precursor protein (APP), presenilin 1 (the enzyme that cuts APP and creates amyloid beta) or tau genes appear to play a crucial role in this process in some cases. This observation has led to the conclusion that events that cause the accumulation of amyloid beta and tau activate a set of downstream cellular signalling and metabolic events that ultimately kill nerve cells.However, attempts using conventional tools to understand why brain cells are killed by the accumulation of these proteins have yielded confusing and conflicting results. We still do not know what types of aggregates formed by these proteins are toxic to brain cells, nor do we know how they disturb the metabolic and signalling machinery inside nerve cells.

Recently, the consortium has developed powerful biophysical and chemical approaches that will allow it to visualise individual aggregate species, to watch which types of aggregates bind to cells, and to identify the downstream pathways that they activate.

Similarly, it has developed a variety of cellular and whole-organism models of these diseases as well as computational and systems biology tools that will allow understanding of how these toxic proteins affect the interlinked network of metabolic and signalling machinery inside nerve cells.

The research programme:

The consortium will apply novel tools from physics,chemistry, computer science, genomics, biology and model organisms to generate a detailed understanding of the molecular mechanics that are activated by the accumulation of amyloid beta and tau, and that ultimately lead to the death of brain cells.

It aims to determine why and how both amyloid beta and tau accumulate in the brains of people with Alzheimer's disease, and why the normal mechanisms for removing aggregated proteins from brain cells become overwhelmed. It will also search for drug-like molecules that stabilise aggregation-prone proteins such as tau as potential therapies for these diseases.

The knowledge and tools generated will provide a rational basis for the future development of diagnostic profiles that could enable doctors to detect the disease in its earliest stages, before irreversible damage is done to the brain, and to personalise and monitor treatment programmes for individual patients, based on the cellular networks that have been disrupted.

Knowledge of these pathways will also provide potential targets for the development of new therapies to repair these pathways, thereby preventing or even reversing the disease.

The team:

PRINCIPAL INVESTIGATOR

Cambridge Institute for Medical Research (CIMR),University of Cambridge

Peter St George-Hyslop

CO-INVESTIGATORS

University of Cambridge

Timothy Bussey (Dept of Experimental Psychology)Damian Crowther (Dept of Genetics)

Christopher Dobson (Dept of Chemistry)

Giorgio Favrin (Dept of Chemistry)

Clemens Kaminski (Dept of Chemical Engineering and Biotechnology)

David Klenerman (Dept of Chemistry)

David Lomas (CIMR)

Cahir O’Kane (Dept of Genetics)

Stephen Oliver (Dept of Biochemistry)

David Rubinsztein (CIMR)

Lisa Saskida (Dept of Experimental Psychology)

Gergely Toth (Dept of Chemistry)

Michele Vendruscolo (Dept of Chemistry)

University of Bristol

Kei Cho

Graham Collingridge

Max-Planck-Unit for Structural Molecular Biology,Germany

Eckhard Mandelkow

Eva-Maria Mandelkow

University of Toronto, Canada

Paul Fraser

Ekaterina Rogaeva

Gerold Schmitt-Ulms

The role of RNA-processing proteins in neurodegeneration

Recent research on motor neurone disease and frontotemporal dementia has shown that RNA-processing proteins are deposited in degenerating nerve cells and that rare mutations in three known genes cause a genetic form of these diseases. Using these discoveries, Professor Shaw and his colleagues from King's College London,Manchester, University of California San Diego,Cambridge and Dundee will model key aspects of the human disorders, allowing them to explore fundamental disease mechanisms and identify new therapeutic targets.

One of three Strategic Awards funded under the WT/MRC Neurodegenerative Diseases Initiative is an innovative research programme exploring the fundamental mechanisms underpinning motor neurone disease and frontotemporal dementia and identifying new therapeutics.

The problem:

Frontotemporal dementia (FTD) is the second most common cause of dementia in the under-65s, and accounts for 10 per cent of all cases of dementia. It causes progressive problems with personality,behaviour and language, and therefore differs from Alzheimer's disease, in which memory problems predominate. The change in behaviour and personality is particularly hard on families. In 40 per cent of cases, other family members are affected and there is a strong genetic basis.

Motor neurone disease (MND) kills 1200 people in the UK every year. It causes muscular weakness that begins in one hand or foot but rapidly spreads to other parts of the body, leaving people paralysed,unable to walk, talk and eat. Patients feel hopeless and helpless. MND is the single most common reason that people seek euthanasia. There are clear genetic links in 10 per cent of cases, but the genes linked to MND account for only 5 per cent of all cases.

There is no treatment for either FTD or MND that can significantly improve survival. All treatment is directed towards controlling symptoms, and to practical and emotional support of the patient and their family. Both disorders are relentlessly progressive and are fatal within three to five years on average.

The questions:

For the past 15 years, it has been known that mutations in the MAPT gene cause FTD with features of Parkinsonism, and that mutations in the SOD1 gene cause MND. These account for only a minority of cases, however. More recently, it has been discovered that the RNA processing proteins TDP-43 and FUS are deposited in nerve cells in the majority of MND and FTD cases, proving that these two diseases are linked through their pathology.

Members of the consortium, led by Professor Shaw,have recently discovered mutations in the genes PGRN, TARDBP and FUS in families with strongly inherited forms of FTD and MND. The challenge now is to understand how these mutations cause disease. It is not known whether they cause disease due to a loss of the protein function or due to a new toxic property acquired by the mutant protein.

The research programme:

The consortium plans to develop cellular and animal models that will allow it to understand what makes nerve cells degenerate and to explore how this process might be reversed.

To investigate the roles of PGRN, TARDBP and FUS, the consortium will make cellular models that have reduced expression of these genes (to test a loss of function) or have mutated genes (to test a toxic gain of function). It will conduct similar experiments in the fruit fly (which will allow it to map out interacting pathways), zebrafish (which will allow it to rapidly screen drugs) and mouse (which, having a mammalian nervous system similar to humans,should giveit the closest disease model). These models can also be used to discover drugs that may slow down or even arrest the disease process in humans.

The consortium also aims to look at the normal function of the proteins produced by these genes and characterise their DNA- and RNA-binding properties, and the functional effects of protein phosphorylation. Lastly it will attempt to repair the defective genes using gene therapy in the cellular and animal models.

The team:

PRINCIPAL INVESTIGATOR

King's College London (MRC Centre for Neurodegeneration Research)

Christopher Shaw

CO-INVESTIGATORS

University of California, San Diego

Don Cleveland (Ludwig Institute for Cancer Research)

University of Cambridge

Jernej Ule (MRC Laboratory for Molecular Biology)University of Dundee

John Rouse (MRC Protein Phosphorylation Unit)

King's College London

Jean-Marc Gallo (MRC Centre for Neurodegeneration Research)

Noel Buckley (Centre for the Cellular Basis of Behaviour)

Corrine Houart (MRC Centre for Developmental Neurobiology)

University of Manchester

Stuart Pickering-Brown (Clinical Neurosciences)

David Mann (Neuroscience Centre)

Understanding Parkinson's disease - lessons from biology

The cause of Parkinson's disease is unknown,although it is clear that it is a disease of ageing and there are now some established genetic risk factors.

To understand how these factors combine, Professors Wood, Hardy and Schapira and colleagues from UCL,Dundee and Sheffield aim to dissect and understand the genetic architecture of Parkinson's and to identify and characterise the biochemical pathways involved in the earliest stages of the disease.

One of three Strategic Awards funded under the WT/MRC Neurodegenerative Diseases Initiative is an innovative research programme dissecting the genetic architecture of Parkinson’s disease and exploring the underlying biochemical pathways to understand the disease pathways involved in the earliest stages of the disease.

To find out more about this collaboration visit the UK Parkinson’s Disease Consortium website.

The problem:

Parkinson's disease is a common neurodegenerative disease that afflicts more than 2 per cent of people aged over 75 years. In the UK, this means there are over 100 000 people with the disease: with the ageing population this number will increase. The annual cost in nursing-home care for Parkinson's disease alone in the UK is estimated to be about￡600-800 million.

Despite tremendous progress in the identification of genes associated with Parkinson’s and related disorders over the last decade, there is still only outline and sketchy information about the molecular pathways involved, and their constituents and their interactions.

Finally, in order to really understand the pathway to human disease, and to be able to influence its progression, the earliest phase needs to be examined.

Thus the consortium will also focus on developing understanding of the very early symptoms or warnings of the illness.

The questions:

The consortium hypothesises that there are multiple causes of Parkinson's, which result in a very small number of separate but converging biochemical pathways. These pathways interact with the molecular pathology of ageing and induce neuronal dysfunction and death, producing the characteristic pathological features of the condition.

It will need to identify all the significant genetic risk factors, and place these molecules and their variants in their pathways to enable it to understand how the human disease begins and develops.

To understand these pathways and mechanisms requires the establishment and integrated use of a range of models.

The research programme:

The consortium aims to achieve a much fuller picture of all the major genetic factors that underlie Parkinson's. It will then identify and characterise the biochemical pathways that these genes determine,and explore their role in the development of disease.

To dissect these mechanisms, the consortium has brought in expertise from mitochondrial biology, cell signalling and Drosophila biology to complement its other model systems.

In parallel it will study the very earliest stages of the illness. It is widely believed that only by understanding these early phases will we be able to modify the disease course for the greatest clinical impact.

To aid this work, the consortium has harnessed the clinical and biochemical resources of the national Gaucher's disease clinic. This will help it to build cohorts of individuals who are genetically at risk;detailed studies of these individuals will include imaging and biochemical assessments.

Over the next five years, the consortium’s plan is to produce detailed knowledge of the molecular pathways that lead to Parkinson’s, and validated markers of its evolution.

The team:

PRINCIPAL INVESTIGATORS

University College London (Institute of Neurology)

Nicholas Wood

John Hardy

Anthony Schapira

CO-INVESTIGATORS

University of Dundee

Dario Alessi (MRC Protein Phosphorylation Unit)

University of Sheffield

Alex Whitworth (MRC Centre for Developmental and Biomedical Genetics)

University College London

Andrey Abramov (Institute of Neurology)

Kailash Bhatia (Institute of Neurology)

J Mark Cooper (Institute of Neurology)

Michael Duchen (Dept of Physiology)

Derralyn Hughes (Royal Free)

Andrew Lees (Institute of Neurological Studies)

Atul Mehta (Royal Free)

Tamas Revesz (Institute of Neurology)

Jan-Willem Taanman (MRC Centre for Neuromuscular Diseases)

Tarek Yousry (MRC Centre for Neuromuscular Diseases)

Sources:

1. Wellcome trust. Our vision. http://www.wellcome.ac.uk/Our-vision/index.htm. Accessed 1 August, 2011.

2. Wellcome trust. Funding. http://www.wellcome.ac.uk/Funding/Biomedical-science/Funding-schemes/Fellowships/index.htm. Accessed 1 August,2011.

3. Wellcome trust. Research opportunities. http://www.wellcome.ac.uk/Funding/Biomedical-science/Application-information/WTD004107.htm.

Accessed 1 August, 2011.