Agency: European Commission | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2015-ETN | Award Amount: 3.90M | Year: 2015
The Phosphoinositide 3-kinase (PI3K) pathway is at the core of multiple fundamental biological processes controlling metabolism, protein synthesis, cell growth, survival, and migration. This inevitably leads to the involvement of the PI3K signalling pathway in a number of different diseases, ranging from inflammation and diabetes to cancer, with PI3K pathway alterations present in almost 80% of human cancers. Therefore, PI3Ks have emerged as important targets for drug discovery and, during 2014, the first PI3K inhibitor was approved by FDA in the US for the treatment of a lymphocytic leukaemia. Nonetheless, our understanding of PI3K-mediated signalling is still poor and only a fraction of the potential therapeutic applications have been addressed so far, leaving a large amount of translational work unexplored. Europe features a set of top quality research institutions and pharmaceutical companies focused on PI3K studies but their activities have been so far scattered. This proposal fills this gap by providing a multidisciplinary network (biochemistry, mouse studies, disease models, drug development, software development) and an unprecedented training opportunity from the bench to the bedside (from pre-clinical discoveries to clinical trials), through cutting edge molecular biology, drug discovery and clinical trial organization. The proposal is aimed at training young investigators in deep understanding of the different PI3K isoforms in distinct tissues and to translate this knowledge into a new generation of PI3K inhibitors, treatment modalities and into identify new uses for existing PI3K inhibitors.
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: PHC-03-2015 | Award Amount: 5.70M | Year: 2016
Hepatocellular carcinoma (HCC) is the most common liver malignancy, with an estimated 750,000 new cases and 695,000 deaths per year, rating third in incidence and mortality in the world. Whilst incidence and mortality for other cancers are declining, HCC represents an increasing public health problem in Europe with men having a higher incidence than women. Several liver diseases lead to HCC and become per definition co-morbidities, such as nonalcoholic steatohepatitis (NASH) or hepatitis B and C virus infection. Most patients die within one year of diagnosis and treatment failure reflects the heterogeneous nature of this tumour, highlighting the need to identify common and co-morbidity specific disease pathways for individualized therapy. HEP-CAR will focus on three leading HCC associated co-morbidities, specifically NASH and hepatitis B and C infection. Non-biased genetic and lipidomic screens will define cellular pathways that are deregulated in HCC and the impact of co-morbidities and gender. Next to established patient cohorts, several in vitro and in vivo models are available to evaluate the role of co-morbidities as drivers of host oncogenic pathways and to provide much needed pre-clinical models for mechanistic studies and future drug screening. We will develop new approaches to study the impact of co-morbidities on HCC immunobiology, ranging from state-of-art tissue explant models to novel humanized mouse models. The aim of HEP-CAR is to define host pathways that impact HCC pathogenesis and to assess their role in different co-morbidities and treatment responses. The research and clinical excellence will be combined with the knowledge transfer and communication competence of leading organizations such as the European Association for the Study of the Liver (EASL) and the European Liver Patients Association (ELPA). Thus, HEP-CAR will generate tangible and sustained improvements in the understanding, prevention and management of HCC for all European citizens.
Berridge M.J.,Babraham Institute
Biochemical Society Transactions | Year: 2012
A wide range of Ca 2+ signalling systems deliver the spatial and temporal Ca 2+ signals necessary to control the specific functions of different cell types. Release of Ca 2+ by InsP 3 (inositol 1,4,5-trisphosphate) plays a central role in many of these signalling systems. Ongoing transcriptional processes maintain the integrity and stability of these cell-specific signalling systems. However, these homoeostatic systems are highly plastic and can undergo a process of phenotypic remodelling, resulting in the Ca 2+ signals being set either too high or too low. Such subtle dysregulation of Ca 2+ signals have been linked to some of the major diseases in humans such as cardiac disease, schizophrenia, bipolar disorder and Alzheimer's disease. © The Authors Journal compilation © 2012 Biochemical Society.
Fearnley C.J.,Babraham Institute
Cold Spring Harbor perspectives in biology | Year: 2011
Calcium (Ca(2+)) is a critical regulator of cardiac myocyte function. Principally, Ca(2+) is the link between the electrical signals that pervade the heart and contraction of the myocytes to propel blood. In addition, Ca(2+) controls numerous other myocyte activities, including gene transcription. Cardiac Ca(2+) signaling essentially relies on a few critical molecular players--ryanodine receptors, voltage-operated Ca(2+) channels, and Ca(2+) pumps/transporters. These moieties are responsible for generating Ca(2+) signals upon cellular depolarization, recovery of Ca(2+) signals following cellular contraction, and setting basal conditions. Whereas these are the central players underlying cardiac Ca(2+) fluxes, networks of signaling mechanisms and accessory proteins impart complex regulation on cardiac Ca(2+) signals. Subtle changes in components of the cardiac Ca(2+) signaling machinery, albeit through mutation, disease, or chronic alteration of hemodynamic demand, can have profound consequences for the function and phenotype of myocytes. Here, we discuss mechanisms underlying Ca(2+) signaling in ventricular and atrial myocytes. In particular, we describe the roles and regulation of key participants involved in Ca(2+) signal generation and reversal.
Le Novere N.,Babraham Institute
Nature Reviews Genetics | Year: 2015
Behaviours of complex biomolecular systems are often irreducible to the elementary properties of their individual components. Explanatory and predictive mathematical models are therefore useful for fully understanding and precisely engineering cellular functions. The development and analyses of these models require their adaptation to the problems that need to be solved and the type and amount of available genetic or molecular data. Quantitative and logic modelling are among the main methods currently used to model molecular and gene networks. Each approach comes with inherent advantages and weaknesses. Recent developments show that hybrid approaches will become essential for further progress in synthetic biology and in the development of virtual organisms. © 2015 Macmillan Publishers Limited.
Okkenhaug K.,Babraham Institute
Annual Review of Immunology | Year: 2013
Phosphoinositide 3-kinases (PI3Ks) control many important aspects of immune cell development, differentiation, and function. Mammals have eight PI3K catalytic subunits that are divided into three classes based on similarities in structure and function. Specific roles for the class I PI3Ks have been broadly investigated and are relatively well understood, as is the function of their corresponding phosphatases. More recently, specific roles for the class II and class III PI3Ks have emerged. Through vertebrate evolution and in parallel with the evolution of adaptive immunity, there has been a dramatic increase not only in the genes for PI3K subunits but also in genes for phosphatases that act on 3-phosphoinositides and in 3-phosphoinositide-binding proteins. Our understanding of the PI3Ks in immunity is guided by fundamental discoveries made in simpler model organisms as well as by appreciating new adaptations of this signaling module in mammals in general and in immune cells in particular. © Copyright 2013 by Annual Reviews. All rights reserved.
Agency: GTR | Branch: BBSRC | Program: | Phase: Research Grant | Award Amount: 487.49K | Year: 2016
CD8+ T cells powerfully coordinate immune responses against intracellular infections and cancer. During immune responses, CD8+ T cells proliferate and differentiate into effector cells that promote elimination of target cells. Effector cells are short-lived and this enables restoration of normal immune function upon resolution of infection. However, a fraction of cells escape this fate and persist to form long-lived memory cells. Memory cells provide a durable self-renewing source of target-specific cells and can persist for decades following infection to generate more efficient secondary responses upon reinfection. CD8+ T cells also become terminally differentiated or exhausted in response to chronic infections and cancer and this impairs their function. Our previous work has identified a key molecular pathway, termed the phosphoinositide 3-kinase (PI3K) pathway, that powerfully regulates CD8+ T cell differentiation. Activation of the PI3K pathway drives widespread changes in gene expression to promote effector differentiation and prevent the formation of memory cells. Mechanisms by which the PI3K pathway causes changes in gene expression are not fully understood. In this study, we will investigate how the PI3K pathway controls the function of a class of proteins called transcription factors (TFs). TFs bind to regulatory regions within DNA and modulate gene expression to control cellular differentiation. We have recently found that the PI3K pathway controls the function of a transcription factor, BACH2, through a process called phosphorylation. We will investigate this new molecular axis, determining how the PI3K pathway regulates the function of BACH2 to control CD8+ T cell responses. Our experimental approach is divided into three components: 1) We will determine the function of BACH2 in regulating CD8+ T cell responses to infection. To do this, we will use a mouse model in which BACH2 is specifically deleted in CD8+ T cells and study immune responses following infection with experimental pathogens. 2) We will determine how the PI3K pathway controls the function of BACH2 to regulate immune responses to infection using a new mouse model in which BACH2 cannot be phosphorylated. We will also determine how BACH2 phosphorylation regulates BACH2 function at a molecular level. 3) We will test the contribution of BACH2 to PI3K-mediated transcriptional programmes in CD8+ T cells. To achieve this, we will utilise mouse genetics to specifically manipulate the PI3K pathway, and regulated transcription factors in CD8+ T cells, measuring consequences of these experimental manipulations on global gene expression and corresponding this data with analyses of transcription factor binding throughout the genome. This work will extend our understanding of how the PI3K pathway exerts such pervasive control over CD8+ T cell differentiation and provide insights into how external cues control gene expression to shape the outcome of immune responses. This will provide targets for development of new vaccine approaches and immune-based therapies for chronic infections and cancer.
Agency: European Commission | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2015-ETN | Award Amount: 3.35M | Year: 2015
ENLIGHT-TEN is a European Network Linking Informatics and Genomics of Helper T cells: our mission is to provide cross-disciplinary training in cellular immunology and big data analysis such that we train a new generation of researchers to fully exploit the power of emerging technological platforms. Our network of TEN beneficiaries combines T cell expertise with state-of-the-art technologies such as next generation sequencing (NGS), bioinformatics, multi-colour flow cytometry, preclinical models and tailored genome editing. Trainees will acquire a comprehensive knowledge in T cell immunology and the capacity to generate and interrogate big data sets as well as expertise in identifying novel biomarkers and developing therapeutic concepts. As such the training programme will provide an ideal stepping-stone for creative and innovative early stage researchers (ESRs) to enter and strengthen Europes academia as well as pharmaceutical and bioinformatics companies. The research focus of the network lies in the identification of extrinsic and intrinsic factors that control development, differentiation and plasticity of helper T cell subsets with particular emphasis on how T cell differentiation impacts on human diseases. The generation of large data sets is an emerging and challenging field, and there is high demand in both the academic sector as well as pharmaceutical companies for researchers to be able to analyse, integrate and exploit this rich source of information. ENLIGHT-TEN will combine the individual strengths of innovative laboratories and enterprises from complementary disciplines to provide unique interdisciplinary training for 13 ESRs, placing them at the forefront of this emerging field. Trainees will be empowered to perform cutting-edge analysis of the steadily increasing number of different T cell subsets, which play highly diverse and critical roles in the development of autoimmune diseases, making them a key target for pharmaceutical companies.
Berridge M.J.,Babraham Institute
Journal of Physiology | Year: 2014
Alzheimer's disease (AD) begins with a decline in cognition followed by neuronal cell death and dementia. These changes have been linked to a deregulation of Ca2+ signalling caused by a progressive increase in the resting level of Ca2+, which may influence cognition by interfering with the rhythm rheostat that controls the sleep/wake cycle. The rise in resting levels of Ca2+ may not alter the processes of memory acquisition during consciousness (gamma and theta rhythms), but may duplicate some of the events that occur during the slow oscillations responsible for the twin processes of memory consolidation and memory erasure that occur during sleep. The persistent elevation in the resting level of Ca2+ induced by an accumulation of amyloid β (Aβ) oligomers duplicates a similar small global elevation normally restricted to the period of slow oscillations when memories are erased during sleep. In AD, such a rapid erasure of memories soon after they are acquired during the wake period means that they are not retained for consolidation during sleep. The Aβ deregulates Ca2+ signalling through direct effects on the neurons and indirectly by inducing inflammatory responses in the microglia and astrocytes. Some of these deleterious effects of Aβ may be alleviated by vitamin D. © 2013 The Physiological Society.
Agency: GTR | Branch: BBSRC | Program: | Phase: Research Grant | Award Amount: 327.03K | Year: 2017
The cells in our body are constantly exposed to chemical and physical stress and accumulate a lifetime of damage to proteins, DNA and various key sub-cellular structures (organelles). It is vital that cells are able to respond appropriately to this damage; failure to do so progressively undermines cellular fitness contributing to age-related declines in cell and tissue function that underpin the normal ageing process and can contribute to age-related diseases such as cancer and dementia. One way that cells respond to stress is to increase the abundance of enzymes that detoxify the cell by removing potentially harmful chemicals. When a cell receives a stress signal the genes that code for detoxifying enzymes are read by transcription factors, discrete proteins that bind to DNA and transcribe the DNA information into RNA molecules, which are in turn translated into the relevant proteins. One such transcription factor, called NRF2, coordinates cellular responses to oxidative stress. Another way in which cells deal with cellular damage is through a process called autophagy (self eating) in which damaged proteins are targeted to cellular recycling centres (called autophagosomes), where they are broken down to their raw materials, which can then be re-used. This process of autophagy requires cargo receptors, which bind to damaged proteins and transport them to the recycling centre for autophagy. These complex processes are orchestrated by signalling pathways within cells that involve cascades of enzymes called protein kinases. These enzymes tag other proteins with a phosphate group (a process called phosphorylation) and this changes the activity, abundance or localisation of the protein. The tagged protein is referred to as the substrate of the protein kinase enzyme. This project concerns two protein kinases, called DYRK1B and DYRK2, and a specific cargo receptor called p62 or sequestosome-1; here well call it p62. Our new results point to a link between the DYRKs and p62 in coordinating how cells respond to stress and damage:- 1. p62 acts as a scaffold to coordinate the activation of the NRF2 transcription factor. We have now discovered that DYRK1B controls the expression of detoxifying enzymes that are known to be targets of NRF2 suggesting that DYRK1B may control activation of NRF2. 2. p62 acts as a cargo receptor for damaged proteins, transporting them to recycling centres for autophagy. It has also been shown that p62 can shuttle in and out of the cell nucleus to collect damaged nuclear proteins for autophagy. This nuclear shuttling requires phosphorylation of p62 but the kinase responsible for this has remained a mystery. We have now discovered for the first time that p62 is phosphorylated by DYRK1B and DYRK2; we propose that this sends p62 into the nucleus to help collect damaged nuclear proteins. 3. p62 coordinates activation of a protein kinase enzyme called mTOR when cells are starved of nutrients. Indeed, mTOR is a critical regulator of lifelong health and controls the lifespan of organisms such as worms, flies, mice and possibly man. Regulation of mTOR by nutrients takes place at specific organelles called lysosomes. However, the phosphorylation of p62 may take it away from lysosomes to the nucleus. Indeed, we find that DYRK2 and p62 co-locate in cells at aggresomes - sites of damaged proteins, consistent with the cargo function of p62. It is not known what effect this re-location of p62 has on nutrient signalling via mTOR at lysosomes. In this study we will define how the DYRKs regulate p62 to coordinate cellular responses to stress and damage. This work is critical to understanding how stress contributes to normal ageing but may also have implications for diseases of old age (dementia, cancer); thus, our results may have wider impacts and we will work with scientists in these areas to progress this.