1 IRELAND Resolving Disorders of Chronic Inflammation Across Europe: Detection, Intervention and Prevention 1. Theme for the Joint Programming Initiative Inflammation is a familiar ally in helping us fight infection. However, almost all ailments that afflict people of developed countries, including those of the EU, are fundamentally disorders of inflammation. Some are well known; the crippling inflammation that affects the joints of rheumatoid arthritis sufferers, for example, results from persistent attack by the body’s own immune defences. Similarly, inflammatory bowel disease (IBD) results from inappropriate and severe responses of our immune systems to gut bacteria. Inflammation is also at the core of many more prevalent conditions and across Europe, atherosclerosis is perhaps most familiar. This is a complex disorder, exacerbated by environment, lifestyle and genetic factors resulting in an inflammatory deposition on blood vessel walls and ultimately in coronary artery disease. Obesity too has an underlying inflammatory component, with adipose and fat tissue harbouring large numbers of inflammatory cells. With obesity now reaching epidemic proportions in many countries, there is growing appreciation of the enormity of its impact on metabolism and its multiple unwanted downstream consequences, including type-2 diabetes. Among the many other conditions with an underlying inflammatory component or origins are neurodegenerative disorders, such as Alzheimer’s disease, a range of allergies, pulmonary disorders and cancers. Major problems Significant increase in inflammatory disorders in the past 20 years across all member states (obesity reaching epidemic proportions) Many of the disorders if left unchecked have the potential to trigger major economical burden due to illness and premature death. Current research efforts are fragmented and don’t include a societal-clinical- scientific framework As distinct as these diseases are, they share many of the same key mechanisms of inflammation. The principal aim of this joint programming proposal is to achieve a cohesive European approach to understanding the similarities and differences in inflammatory processes across broad sectors of disease. In so doing, joint programming would to bring together the strands of research, clinical expertise and therapeutic approaches and approaches of different healthcare systems. When considered together, inflammation-based diseases continue to present a growing problem of immeasurable socio-economic proportions. Research funding invested by individual nations each year into the fundamental aspects of inflammation are considerable; Focus is intensive at the molecular and cellular levels, as well as in how this applies to the broader pathophysiology of a diverse array of diseases. Importantly, considerable research dollars and Euros are also spent in untangling the complex risk factors and genetic associations that underpin many conditions and diseases. PRIMARY GOALS A classification of key those factors (societal, environmental, genetic) that increase inflammatory disease onset Improved understanding of key inflammatory pathways across diseases, shared and distinct mechanisms. Development of diagnostics and medical devices that allow for early diagnosis The development of drugs and therapeutics that will promote recovery 2 2. Proposing GPC member/members Ireland and 3. Objectives The proposal recognises three broad themes underpin the challenge posed by inflammatory diseases collectively representing significant social, clinical and scientific challenges. 1. Detection- Improved detection of common and distinct pathways of pathways will build on capacity in basic research in common mechanisms of inflammation, genetics of disease susceptibility, biosensors and population and individual level monitoring of disease and of inflammation. 2. Intervention – Through a more comprehensive investigation of the inflammatory responses associated with the disease sectors at basic scientific and clinical levels, the mechanisms of the disease will be identified. Effective treatments and interventions for chronic inflammatory diseases remain a priority and outputs from basic and clinical work will help identify targets and new therapies developed. In addition, effective intervention will explore new modes of drug formulation and delivery. 3. Prevention- Ultimately, the premise is that many of inflammatory diseases are preventable, with changes to lifestyles and improved understanding of risk factors making a significant difference. The prevention of disease in the first place must always be a chief goal, but realistically cannot be pursued in the absence of better understanding of disease mechanisms, risk factors, genetics, pathophysiology and diagnosis culminating from objectives 1 and 2. 3 4. Research Questions To Be Addressed The programming research questions will focus on better detection across two broadly defined disease sectors: gastrointestinal disorders and obesity and metabolic diseases. The overarching concept is that with shared and distinct mechanisms of inflammation underlying each disease, a comparative approach to understanding their genetics, distinct and common inflammatory pathways and pathophysiology will ultimately lead to more accurate detection and early diagnosis. Thus, uniting the two disease sectors are the common goals of detection, intervention and prevention. The disease areas affect EU countries differently and variation will also exist in the strengths and capacity between member states in the priorities of basic research, medical care and initiatives aimed at improving lifestyle and environment. For this reason, it is anticipated that a JPI in this area would have particular benefits in drawing the priorities and relative strengths of different contributing members together in a productive and effective manner. Obesity Prevention and Detection Gastro-Intestinal Metabolic Disorders Disorders Intervention 4.1 Obesity and Metabolic Disorders 4.1.1 Chronic Inflammation and Obesity In recent years it has become evident that inflammatory responses play a central role in obesity and its associated disease states (type II diabetes, atherosclerosis). Our body’s adipose tissue provides a flexible storage depot for excess nutrients, in addition the adipose tissue is also responsible for the release of cytokines that regulate energy within the body. However, when the adipose tissue’s ability to store lipid and regulate nutrient metabolism becomes imbalanced due to the presence of excess nutrient inflammatory marker expression increase, initiating an inflammatory response. In the US a study on childhood obesity identified a dramatic rise in the prevalence of obesity in the space of two decades, from about 5% in 1980 to 20% in 2000. What was also noted in this study was that that during this same time period allergic response to skin tests has almost doubled in children from 22% to 42% in children. Visness et al examined the results from the National Health and Nutrition Examination Survey 2005-2006 in the US and identified that. Allergies were more prevalent among obese and overweight children. Obesity was associated with chronic inflammation. Allergy was also associated with inflammation. Our understanding of complex relationship between inflammation, obesity and disease progression is still very much in its infancy and the research in this area requires a coherent structured approach considering the scale of the problem (see below). 4 Why does Obesity require a Joint Programming Approach? The prevalence of obesity is currently on the rise in almost all industrialized countries and has become such a prominent problem that many countries have set up national taskforces (Ireland, Australia, Greece, UK), in addition to the already established international obesity task force (IOTF http://www.iotf.org/index.asp). The most worrying statistic is that childhood obesity has reached epidemic proportions in Europe, with body weight now the most prevalent childhood disease. In a 2005 EU platform paper on obesity, the Mediterranean islands of Malta, Sicily, Gibraltar and Crete as well as the countries of Spain, Portugal and Italy reported overweight and obesity levels exceeding 30% among children aged 7-11. In addition England, Ireland, Cyprus, Sweden and Greece report levels above 20%, while France, Switzerland, Poland, the Czech Republic, Hungary, Germany, Denmark, Netherlands and Bulgaria reported overweight levels of 10- 20% among this age group. In Ireland there is thought to be in the region of 300,000 overweight and obese children with this number rising by a rate of over 10,000 per year. In Europe this rate of increase is thought to be in the region of 400,000 children per year. Because obesity is associated with premature death, excessive morbidity and serious psychosocial problems the damage it causes to the welfare of citizens is extremely serious and for this reason a concerted intervention is necessary and warranted. In 2009 it is believed that 2,000 premature deaths in Ireland will be attributed to obesity with this number set to rise in future years. In addition to the in care hospital costs, obesity results in many indirect costs such as days lost to the workplace due to illness arising from obesity and output foregone as a result of premature death and this is estimated to cost Ireland alone approximately €4 billion per year. 4.1.2 Type II Diabetes Obesity is a major risk factor for the development of type II diabetes. Type II diabetes accounts for approximately 90% of cases of diabetes and is characterised by insulin resistance in combination with dysfunction of insulin producing cells. Insulin is a hormone produced by the pancreas that plays an essential role in regulation of blood sugar levels. Individuals with diabetes fail to make insulin (Type I diabetes) or to respond to it (type II diabetes) resulting in elevated blood glucose levels. Long term complications of diabetes include damage to the blood vessels, eyes, kidneys, and nerves. Early diagnosis and appropriate management, such as increased exercise and dietary modification, is essential to reduce the occurrence of these complications. Chronic low grade inflammation underlies the pathogenesis of type II diabetes and circulating markers of inflammation, such as IL-6 and C-reactive protein (CRP), are strong predictors of development of the disorder. Many of these inflammatory markers, such as CRP, are also shared with CVD and it is now believed that activation of inflammation is a common antecedent to both Type II diabetes and CVD. Patients with Type II diabetes are at an increased risk of developing CVD. The exact effect of these inflammatory markers on glucose metabolism is still unclear but it is clear that cytokines such as IL-6 and TNF can directly interfere with insulin signaling. Early studies also indicate that anti-inflammatory drugs, such as salsalate, may help prevent type II diabetes. Why does Type II Diabetes require a Joint Programming Approach? We are currently in the midst of a diabetes epidemic. The International Diabetes Foundation has estimated that the number of people affected will increase by more than 50% in the period from 2003-2025, with a predicted 333 million people affected by 2025. Both industrialized and developing countries will be affected. In the US prevalence rates have doubled between 1990 and 2005 and the Centre for Disease Control (CDC) has characterized the increase as an epidemic. Within Europe an increase from 7.8% to 9.1% (58.1 million persons) is predicted. In a study by the International Diabetes Federation-European Region (IDF-Europe) and the Federation of European Nurses in Diabetes (FEND), the prevalence of diabetes is predicted to rise from 7.5% to 16% over the next 20 years with an increasing prevalence of Type 2 diabetes being the main driving force behind the increase. In the Republic of Ireland, the WHO estimated that in 2000 there were 86,000 cases of diabetes with the number of cases expected to rise to 157,000 by 2030. In 2005, 141,063 adults in the Republic of Ireland (4.7%) had diabetes (diagnosed or undiagnosed). 5 Type II diabetes has traditionally been considered an adult disorder. However, the prevalence of this disorder within children is particularly on the rise, in parallel to rising obesity rates and altered dietary and life style factors during childhood. Genetic factors also interact with these environmental factors to determine the overall individual risk of developing the illness. A greater understanding of the causative genetic factors will reveal the mechanistic basis of this metabolic disorder. This JPI is therefore timely and will build upon the recent large scale genomic studies to develop new diagnostics and therapies. 4.1.3 Ireland’s Contribution to Research in the Area of Obesity and Metabolic Diseases Ireland has set up a national task force to specifically address the issue of obesity and related disorders and in doing so have identified the scale of the problem that the will face if the spread of the disease is left unchecked. To this end an evaluation of the population, their diets, lifestyles and social settings is beginning to identify communities, population clusters and individuals that are at most risk of becoming obese and thus having the secondary development of type-II diabetes and other secondary disease. At a basic research level Ireland has invested approximately €10 million in this past ten years in basic and clinical research in projects mainly focused on the characterization of specific problems associated with diabetes (diabetic nephropathy, diabetic retinopathy, circulation) and the development of diagnostics (Prof Holthofer DCU). From the economic burden described above then it is readily apparent that as a nation there is a significant under spend in research within these areas. Ireland does have specific expertise in certain areas, however, we do not have the capacity to effectively combat a problem of an epidemic proportion. 4.2 Gastro-Intestinal Inflammatory Disorders The mucosal immune system of the gastrointestinal tract (GI tract) plays a key role in preventing pathogens from entering the body and maintaining the delicate balance with the gut micro-flora. Inappropriate activation of the mucosal immune system contributes to the development of a number of chronic inflammatory disorders, such Inflammatory Bowel Disease (IBD) 4.2.1 Inflammatory Bowel Disease Crohn’s Disease (CD) and Ulcerative Colitis (UC), collectively known as Inflammatory Bowel Disease (IBD), are chronic inflammatory disorders of the intestine resulting in symptoms such as abdominal pain, diarrhea, vomiting or weight loss (CD) or constant diarrhea mixed with blood, of gradual onset (UC). Treatment options are restricted to controlling symptoms, inducing remission and preventing relapse although UC can be cured by surgical removal of the colon. Years can elapse prior to accurate diagnosis of IBD and given increased risk of bowel obstruction, malnutrition and cancer, early detection is crucial. The underlying pathophysiology of IBD remains to be elucidated. However, it is likely to involve a complex interplay between genetic, microbial, and environmental factors resulting in a sustained activation of the mucosal immune system and chronic inflammation/tissue damage. Genetic changes responsible for conferring susceptibility are currently under investigation. DNA variants in the NOD2/CARD15 gene, which has known functions in bacterial recognition, apoptosis and inflammatory signaling, look promising. Environmental triggers may include improved hygiene and reduced exposure to intestinal pathogens in addition to cigarette smoking, all of which may affect development of the humoral immune system. Indeed, it is believed that the fundamental defect in IBD is an overactive mucosal immune system which, in genetically susceptible individuals, inappropriately reacts to normal constituents of the mucosal microflora. Why does IBD require a Joint Programming Approach? IBD affects 15,000 people in Ireland, 130,000-140,000 people in the UK and millions worldwide. The incidence (annual diagnosis rate) of CD varies from 0.5-24.5/100,000 inhabitants with prevalence rates (estimated rate of population affected) as high as 396/100,000 inhabitants. IBD is an important public health problem as it afflicts young people, typically females in their child bearing years, and has a protracted and relapsing clinical course. 6 The prevalence of IBD has been steadily increasing in the US and Europe over the past 20-50 years (Juillerat et al. 2008, Armitage et al. 2001, Jacobsen et al. 2006) with rises as much as 30% reported. The rising prevalence of IBD may be a feature of developing nations or urbanisation and a recent report suggests that eastern European countries are now experiencing increasing incidence rates for both CD and UC (reviewed by Lakatos and Lakatos, 2009). In Europe, CD has now become one of the commonest chronic diseases. Since it mainly affects young adults and has a chronic and progressive course, this disease presents a significant social and economic burden. In terms of health care costs, a recent German study estimated mean 4-week costs per patient of €1425 and €1015 for CD and UC, respectively (Stark et al. 2006). The cost of IBD to the NHS has been estimated at about £720 million per annum, based on the prevalence and an average cost of £3,000 per year per patient. These lifelong healthcare costs are comparable to those for major chronic disorders such as cancer and diabetes. There is currently no cure for CD and early detection is critical to prevent further pathology, associated disorders, such as colorectal cancer, and increased mortality. 4.2.2 Celiac Disease Celiac disease in an inherited autoimmune disorder triggered by the digestion of gluten resulting in an inappropriate immune response against the small intestine, resulting in chronic inflammation and inhibition of absorption of important nutrients. Patients typically present with chronic diarrhoea, weight loss and anaemia, in addition to extra-digestive symptoms, such as infertility and skin lesions. However, many patients are actually asymptomatic. Such a variable presentation has resulted in difficulties diagnosing this chronic disorder and it is estimated that only 10-20% of cases in Europe and the US have been diagnosed. Early diagnosis is essential to reduce patients’ risks of developing other autoimmune disorders, neurological problems, osteoporosis and cancer in addition to increased mortality. A gluten-free diet is currently the only form of treatment. Celiac disease is a multi-organ inflammatory disorder of multi-factorial aetiology. Familial studies have revealed a genetic basis for this disorder and the human leukocyte antigen (HLA) class II DQA and DQB genes are the principal determinants of genetic susceptibility. These genes encode products that are responsible for presenting gluten (environmental trigger) to immune cells. Why is celiac disease of significant concern? An estimated 2.5 million Europeans suffer from celiac disease (approximate prevalence of 1%). However, this figure is on the rise. For example, a recent population-based cohort study in Finland reported a doubling in prevalence in the last two decades, which now stands at 2% (Lohi et al. 2007). This disorder is a major public health problem because of its high prevalence and long- term complications. Patients can be affected at any age, including during childhood, resulting in a considerable life long disease burden. Furthermore, patients are at an increased risk of developing other autoimmune disorders, such as Type I Diabetes, systemic lupus erythmatosus, and rheumatoid arthritis in addition to risk of seizures, short stature and cancer. Accurate diagnosis is one of the major challenges facing patients and physicians. The disorder can be very difficult to diagnose which has resulted in a low level of detection. Intestinal biopsy remains the gold standard for diagnosis, although serological tests of varying sensitivity and specificity are available. Adherence to a strict gluten-free diet, the only form of “treatment” available to patients, is extremely difficult as gluten is present in many foods as an additive or contaminant. The long-term consequences of a gluten-free diet are also unclear. Furthermore, gluten-free foods have poor availability and are more expensive than their gluten-containing counterparts. These issues significantly impact on dietary compliance and the quality of life for sufferers of celiac disease. CDEUSSA is a specific support action from FP6 that aims to identify the major issues in the areas of treatment, prevention and public health in the area of celiac disease. A number of stakeholder events have been held resulting in prioritization of the following areas: development of primary prevention and new treatment strategies for celiac disease in addition to revised diagnostic criteria (Troncone et al. 2008). This JPI can build upon the foundations laid by this EU initiative. 7 4.2.3 Ireland’s Contribution to Research in the Area of Gastro-intestinal Inflammatory Disorders This JPI will build upon existing strengths in Ireland in the areas of inflammation, GI disorders and diagnostics. SFI has invested over €70 million in inflammation and GI disorders and approximately €38 million in diagnostics and biosensors. This investment has resulted in the development of a number of world class research centres in highly relevant areas, such as the Immunology Research Cluster, Alimentary Glycoscience Cluster, Alimentary Pharmabiotic Centre in addition to the Biomedical Diagnostics Institute and a number of nanotechnology research centres. Ireland also has a number of indigenous companies in the medical diagnostics sector. Therefore, Ireland is well placed to lead the development of diagnostics for early detection of chronic inflammatory disorders and to maximize the impact of the investment in this area to date. 4.3 Overview of Ireland’s Contribution to Research in the Area of Chronic Inflammation Immunology has emerged as an area of significant research strength in Ireland over the last ~10 years, partly due to funding from SFI and the HRB. SFI has awarded more than €70 million in grants to world class Irish researchers investigating inflammatory disorders of the respiratory and gastrointestinal tracts in addition to studies of host-microbe interactions, which as highlighted earlier, play a crucial role in normal development of the immune system. In addition to a large number of Principal Investigator awards, we have funded a number of highly relevant clusters of academic and industrial researchers under our Centres for Science, Engineering and Technology (CSET) and Strategic Research Cluster (SRC) programmes which would provide important building blocks for this JPI. The Immunology Research Cluster (IRC SRC) led by Prof. Kingston Mills and based in Trinity College Dublin has been awarded €7.5 million to investigate and exploit the interface between the innate and adaptive immune system. This cluster of researchers specifically aims to develop anti- inflammatory agents to treat autoimmune disorders and has developed a number of collaborations with industry to achieve its aims (e.g. Opsona Therapeutics, Scherring Plough). The Alimentary Glycoscience Research Cluster was founded in 2009, under the lead of Prof. Lokesh Joshi under the SFI SRC programme (€5.1 million award). The aim of this cluster is to investigate the glycomic responses of gut cells to pathogenic and probiotic microorganisms and milk oligosaccharides and is comprised of leading researchers from universities throughout the republic of Ireland. The Alimentary Pharmabiotic Centre (APC, CSET), led by Prof. Shanahan at University College Cork, has received €38 million from SFI and aims to investigate the means by which intestinal bacteria influence health and disease and develop new therapies for lifelong debilitating gastrointestinal diseases such as gastroenteritis, ulcerative colitis, and Crohn’s disease. To help achieve these aims, APC have developed industrial collaborations with Alimentary Health and GlaxoSmithKline. Alimentary Health developed AlignTM, the only probiotic currently on the market that demonstrates efficacy in the treatment of Inflammatory Bowel Syndrome. Ireland has also developed significant research strengths in the area of medical devices/diagnostics and SFI actively funds research in the area of biosensors and diagnostics (in excess of €18.5 million to date) under many of our award programmes, including CSET. In particular, the Biomedical Diagnostics Institute led by Prof. Brian McCraith was funded under our CSET programme in 2005. The BDI is a multidisciplinary research institute focused on the development of next generation point-of-care biomedical diagnostic devices. Ireland has also made significant funds in regenerative medicine with obvious implications for therapies in inflammatory disorders. In particular the Regenerative Medical Institute SFI funded CSET based in the National University of Ireland Galway has interests in regenerative capacity of adult stem cells to in diseases with strong inflammatory components, including cardiovascular disease and osteoarthritis. 8 Ireland has significant research strengths in the areas of immunology and biosensors/biomedical diagnostics in both the academic and industrial sectors. SFI have funded two CSETs and 2 SRCs and a large number of principal investigators in areas relevant to this JPI. Some examples are listed below: Principal Investigator Research Focus Cormac Taylor (UCD) Intestinal models of drug uptake and delivery/Developed a drug for IBD in collaboration with Sigmoid Biotechnologies Lothar Steidler (APC/UCC) Development of genetically engineered Lactococcus lactis that secrete bioactive cytokines/Clinical trial for treatment of IBD Christine Loscher (DCU) The role of dietary fatty in modulating Th1-mediated disease Jakki Cooney (UL) Role of bacterial proteases in gut health and disease Brendan Loftus (UCD) Genomics of host-microbe interactions Luke O’Neill (TCD) Innate immunity and inflammation 4.4 Overview of Ireland’s Contribution to Research in the Area of Diagnostics Ireland has also developed significant research strengths in the area of medical devices/diagnostics and SFI actively funds research in the area of biosensors and diagnostics (in excess of under many of our award programmes, including CSET. Ireland has also recognized strengths in nano-technology applications for the Life Sciences sector with possible uses in the development of diagnostics and sensors (in excess of €20 million SFI investment). Diagnostics The Biomedical Diagnostics Institute (BDI: http://www.bdi.ie/) led by Prof. Brian McCraith was funded under our CSET programme in 2005 (€16.5 million investment with €6.5 million investment from industry partners). The BDI is a multidisciplinary research institute focused on the development of next generation point-of-care biomedical diagnostic devices for monitoring indicators of chronic diseases, including self-test, home use. There are 6 core industrial partners involved with BDI including Becton Dickinson and Co., Analog Devices Inc. and Enfer Technologies Inc. Ireland also has a number of home grown companies with a focus on diagnostics, such as Biotrin and Trinity Biotech. Biosensors Expertise in the area of biosensors includes Prof. John Lowry (National University of Ireland at Maynooth) who is developing sensors and biosensors to develop neurochemicals in the living brain, technological developments which could be also applicable to chronic inflammatory disorders. The Technology Research for Independent Living (TRIL: http://www.trilcentre.org/) research centre, which aims to assist older people in living from home, is developing the technology required for remote sensing. We also have significant expertise in the application of nanotechnology/nanoscience to the development of biosensors (see below). Nanotechnology Ireland is noted for its significant strengths in nanotechnology and nanoscience. A number of world class research centres devoted to research in these domains have been established, such as the CRANN nanoscience research centre, Tyndall and the BioNanoInteract Strategic Research Cluster. The CRANN centre has a research programme focused on development of bio-nano- sensors of relevance to medical diagnostics and imaging devices and has built industry partnerships with major multinationals, such as Intel and Hewlett Packard. Strengths in the nano- technology development and characterization of nano-materials, with potential uses in medical diagnostics, include the Tyndall research centre, and a cluster of researchers based at University College Dublin (UCD). This cluster includes Prof. Suzi Jarvis (Nanoscale Function group), Prof. Gill Lee (BioNanoTechnology research group with a focus on development of lap-on-a-chip devices) and the Centre for BioNanoInteractions (http://www.cbni.eu/), one of the world's leading Centres of Knowledge in bionanointeractions applied to the fields of nanosafety, nanobiology and nanomedicine. This centre was funded through the SFI SRC programme. 9 4.5 Timescales and Targets for JPI on Chronic Inflammatory Diseases Detection 2013 onwards: A 3 – 4 year period would is envisaged for us to begin to generate medical devices and diagnostics that could accurately detect the early development of many of the disease states. A further 2 years may be required for the development of these into commercially available, easy to use kits that can be widely used either at home or under the supervision of medical practitioners. Intervention 2014 onwards – The effective treatment of chronic inflammatory diseases will come form a better understanding of disease mechanisms. Given that even if we identify drugs with great potential at a very early stage these compounds therapeutic strategies will require a very detailed characterization before they can be widely used. Prevention 2011 onwards: Programmes and initiatives that tackle the prevention of diseases might be envisaged begin almost immediately. It is hoped from the collaborating of large scale epidemiological data from each of the participating states within this JPI that we would be able to clearly establish those societal, environmental and genetic factors that are of greatest significance for an increased prevalence of each of the disorders within various sub populations. Milestone Time line 2011 2012 2013 2014 2015 2016 2017 Detection Markers, Mediators, Devices and Diagnostics (e.g. prototype diagnostic kits for Type-II diabetes) Intervention Drugs and Therapeutics (e.g. 1st phase clinical trials) Prevention Risk factors and Education (e.g. structured education on health for school children) 5. Added-Value, Benefits and Impact Benefits and impact of a JPI under the proposed theme for European citizens and European competitiveness as well as other benefits JP approach might bring to addressing the proposed theme. The value added to overall current research financed from national and Community public funds and its potential to increase the efficiency and impact of public R&D financing. Inflammation research and immunology have emerged as areas of significant research strength in Ireland over the last ~10 years. SFI has awarded more than €80 million Euro in grants to world class Irish researchers investigating inflammatory mechanisms of relevance to obesity, metabolic and GI disorders, in addition to studies of host-microbe interactions, which play a crucial role in normal development of the immune system. As well as a large number of Principal Investigator awards, we have funded many highly relevant clusters of academic and industrial researchers under our Centres for Science, Engineering and Technology (CSET) and Strategic Research Cluster (SRC) programmes. This substantial investment by national agencies has created a group of world class research immunology researchers in Ireland. The proposed JPI would maximize the current investment by coordination of Irish researchers towards a common grand EU challenge. This would not only result in a more focused and aligned research strategy, but would also allow Irish researchers even greater access to areas of expertise that are not particular strengths in Ireland. Equally, the capacity of Ireland in this area would represent an important contribution to 10 inflammation-based research in other countries in the EU. Ultimately, this will result in more efficient and productive research programmes, with a greater potential impact from public R&D spend. Is this a problem that really requires a long-term sustained effort/investment with political buy-in to effectively tackle it? If the inflammatory disorders detailed above (obesity, type-II diabetes, Crohn’s disease, and celiac disease) were specific to a single nation then a more specialized approach may be required. The fact that the majority of these disorders are increasing across the EU and in much of the industrialised world is itself indicative of the requirement for a JP in this area. When the term epidemic is used in relation to childhood obesity, and the figures considered across the EU , the percentage of the young population that are considered obese reveal themselves in frightening proportions. The broader socio-economic burden to broader society including the workforce is equally disturbing. Currently, many of the major questions addressed above cannot be effectively answered at a national level due to fragmented scientific and clinical research activities. Therefore, a clear cohesive and international approach is required. This would allow specialised scientists, clinicians and epidemiologists within each of the disease areas to combine their efforts to effectively reduce the incidence of the disease, provide effective diagnostics and more effectively treat the disorders, Is this a problem that really requires a long-term sustained effort/investment with political buy-in to effectively tackle it? Strong evidence shows that many of the inflammatory disorders and especially those discussed in this proposal are on the increase, with the most striking rise occurring in the female population. The area of obesity has received a major political buy-in already, with many countries setting up national task forces to deal with the problem. Therefore, there is an apparent realisation at a political level that the societal and economic burden of these disorders in the future is on a dangerous trajectory. This can only serve to strengthen the argument for a sustained effort/investment to effectively tackle the problem at an EU level is required. 6. Preliminary suggestions concerning the governance and implementation State the level of the envisaged involvement of the participating countries. Provide preliminary suggestions on the common vision, governance structure and the implementation of the proposed JPI. Such information could include, among others: Envisaged participation Recognising the investments already being undertaken members states in research related to these disease areas, participation would aim to most effectively link national research programmes in basic inflammation research and those related to the specific disease areas. It is recognized that the states will have different priorities in disease areas, and different levels of in terms of programmes for diagnosis and treatment as well as potential national programmes in disease prevention. Governance and management Ireland has taken an active role in the pilot JPI on Alzheimer’s disease and we would support a similar structure (outlined below) being adopted for the current JP. The management structure would be composed of: the Management Board, an Executive Board, a Scientific Advisory Board and a Secretariat. The Management Board will from the primary decision making body and will seek advice from the Scientific Advisory Board on the Strategic Research Agenda and related matters. The Executive Board will support the Management Board in all aspects concerning the preparation and implementation of decisions. The Secretariat will organize the day to day management of the management structure and implement those tasks assigned to it by the Management Board and the Executive Board. Any Member State of the EU (MS) or any State associated to the European Framework Programme (AS) willing to participate in the JPI can be represented with all participating States represented in the Management Board. The membership of those States 11 joining the Initiative later than the constitutive meeting shall be approved by the Management Board. If more than 10 countries wish to participate in the JP, an Executive Board shall be established among the members of the Management Board and its mission will be to assist - To assist the Management Board by preparing meetings, proposals for actions and strategy, allowing the Management Board to focus on strategic decisions. - To ensure proper implementation of the Management Board decisions and to monitor follow-up of the action lists established by the Management Board - To oversee the work of the Secretariat and specify the tasks to be carried out by it The tasks of the Executive Board will be specified by the Management Board and the Executive Board will report on a regular basis to the Management Board. The Scientific Advisory Board shall assist the Management Board in establishing the Strategic Research Agenda (SRA), and propose scientific priorities based on societal needs and scientific evidence. It shall support the management board activities to implement the SRA according to a realistic timeline. In consensus with the Executive Board and with the help of the Secretariat, the Scientific Advisory Board may invite collaborative ad-hoc working groups of experts and/or relevant stakeholders were necessary to support them in their tasks. How might this JPI work? To ensure success, a JP on chronic inflammation would require a transparent and open agreement between all member states to allow for the rapid transfer of knowledge between sectors. In particular, to effectively reduce the prevalence of these diseases, any large scale epidemiological studies covering societal, environmental and genetic factors will be coordinated. Identify those sub population of individuals and educate/treat them effectively. Approximate duration of the research activities; In order for the JPI to be effective an initial extensive 5 year programme will be required to target many of the inflammatory disorder outlined above. Following this initial 5 year period it would be hoped that a significant proportion of the research studies could be significantly reduced as it would be hoped that many of our major goals would be achieved in that time period. However, in order to see an effective return on the initial investment a continuation of the JP would be envisaged for a further 10 -15 years in order to establish if the measures taken are effectively reducing the prevalence of many of the disorders Openness to additional participant countries at a later stage, taking into account the principle of open access as referred to in paragraph 7 of the Council conclusions Openness and inclusion is a necessity for the success of this JP and as many member states as possible would actively be encouraged to participate in this JPI. Chronic inflammation and the associated disorders is a serious problem in all the EU member states as highlighted above. Therefore a coherent and concerted effort is required to address the many issues relating to the increased prevalence of inflammatory diseases and their mechanism’s of action. In taking action now we can reduce the significant health and economic burdens that will undoubtedly affect the EU member states in the not very distant future if no action is taken.
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