Project acronym CANBUILD
Project Building a Human Tumour Microenvironment
Researcher (PI) Frances Rosemary Balkwill
Host Institution (HI) QUEEN MARY UNIVERSITY OF LONDON
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary Even at their earliest stages, human cancers are more than just cells with malignant potential. Cells and extracellular matrix components that normally support and protect the body are coerced into a tumour microenvironment that is central to disease progression. My hypothesis is that recent advances in tissue engineering, biomechanics and stem cell biology make it possible to engineer, for the first time, a complex 3D human tumour microenvironment in which individual cell lineages of malignant, haemopoietic and mesenchymal origin will communicate, evolve and grow in vitro. The ultimate aim is to build this cancerous tissue with autologous cells: there is an urgent need for models in which we can study the interaction of human immune cells with malignant cells from the same individual in an appropriate 3D biomechanical microenvironment.
To achieve the objectives of the CANBUILD project, I have assembled a multi-disciplinary team of collaborators with international standing in tumour microenvironment research, cancer treatment, tissue engineering, mechanobiology, stem cell research and 3D computer-assisted imaging.
The goal is to recreate the microenvironment of high-grade serous ovarian cancer metastases in the omentum. This is a major clinical problem, my lab has extensive knowledge of this microenvironment and we have already established simple 3D models of these metastases.
The research plan involves:
Deconstruction of this specific tumour microenvironment
Construction of artificial scaffold, optimising growth of cell lineages, assembly of the model
Comparison to fresh tissue
Investigating the role of individual cell lineages
Testing therapies that target the tumour microenvironment
My vision is that this project will revolutionise the practice of human malignant cell research, replacing misleading systems based on cancer cell monoculture on plastic surfaces and allowing us to better test new treatments that target the human tumour microenvironment.
Summary
Even at their earliest stages, human cancers are more than just cells with malignant potential. Cells and extracellular matrix components that normally support and protect the body are coerced into a tumour microenvironment that is central to disease progression. My hypothesis is that recent advances in tissue engineering, biomechanics and stem cell biology make it possible to engineer, for the first time, a complex 3D human tumour microenvironment in which individual cell lineages of malignant, haemopoietic and mesenchymal origin will communicate, evolve and grow in vitro. The ultimate aim is to build this cancerous tissue with autologous cells: there is an urgent need for models in which we can study the interaction of human immune cells with malignant cells from the same individual in an appropriate 3D biomechanical microenvironment.
To achieve the objectives of the CANBUILD project, I have assembled a multi-disciplinary team of collaborators with international standing in tumour microenvironment research, cancer treatment, tissue engineering, mechanobiology, stem cell research and 3D computer-assisted imaging.
The goal is to recreate the microenvironment of high-grade serous ovarian cancer metastases in the omentum. This is a major clinical problem, my lab has extensive knowledge of this microenvironment and we have already established simple 3D models of these metastases.
The research plan involves:
Deconstruction of this specific tumour microenvironment
Construction of artificial scaffold, optimising growth of cell lineages, assembly of the model
Comparison to fresh tissue
Investigating the role of individual cell lineages
Testing therapies that target the tumour microenvironment
My vision is that this project will revolutionise the practice of human malignant cell research, replacing misleading systems based on cancer cell monoculture on plastic surfaces and allowing us to better test new treatments that target the human tumour microenvironment.
Max ERC Funding
2 431 035 €
Duration
Start date: 2013-06-01, End date: 2018-05-31
Project acronym CARDIONECT
Project Cardiac Connective Tissue: Beat-by-Beat Relevance for Heart Function in Health and Disease
Researcher (PI) Peter Kohl
Host Institution (HI) UNIVERSITAETSKLINIKUM FREIBURG
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary Cardiac connective tissue is regarded as passive in terms of cardiac electro-mechanics. However, recent evidence confirms that fibroblasts interact directly with cardiac muscle cells in a way that is likely to affect their beat-by-beat activity.
To overcome limitations of traditional approaches to exploring these interactions in native tissue, we will build and explore murine models that express functional reporters (membrane potential, Vm; calcium concentration, [Ca2+]i) in fibroblasts, to identify how they are functionally integrated in native heart (myocyte => fibroblast effects). Next, we will express light-gated ion channels in murine fibroblast, to selectively interfere with their Vm (fibroblast => myocyte effects). Fibroblast-specific observation and interference will be conducted in normal and pathologically remodelled tissue, to characterise fibroblast relevance for heart function in health & disease.
Based on these studies, we will generate 2 transgenic rabbits (fibroblast Vm reporting / interfering). Rabbit cardiac structure-function is more amenable to translational work, e.g. to study fibroblast involvement in normal origin & spread of excitation across the heart, in pathological settings such as arrhythmogenicity of post-infarct scars (a leading causes of sudden death), or as a determinant of therapeutic outcomes such as in healing of atrial ablation lines (interfering with a key interventions to treat atrial fibrillation).
The final ‘blue-skies’ study will assess whether modulation of cardiac activity, from ‘tuning’ of biological pacemaker rates to ‘unpinning’ / termination of re-entrant excitation waves, can be achieved by targeting not myocytes, but fibroblasts.
The study integrates basic-science-driven discovery research into mechanisms and dynamics of biophysical myocyte-fibroblast interactions, generation of novel transgenic models useful for a broad range of studies, and elucidation of conceptually new approaches to heart rhythm management.
Summary
Cardiac connective tissue is regarded as passive in terms of cardiac electro-mechanics. However, recent evidence confirms that fibroblasts interact directly with cardiac muscle cells in a way that is likely to affect their beat-by-beat activity.
To overcome limitations of traditional approaches to exploring these interactions in native tissue, we will build and explore murine models that express functional reporters (membrane potential, Vm; calcium concentration, [Ca2+]i) in fibroblasts, to identify how they are functionally integrated in native heart (myocyte => fibroblast effects). Next, we will express light-gated ion channels in murine fibroblast, to selectively interfere with their Vm (fibroblast => myocyte effects). Fibroblast-specific observation and interference will be conducted in normal and pathologically remodelled tissue, to characterise fibroblast relevance for heart function in health & disease.
Based on these studies, we will generate 2 transgenic rabbits (fibroblast Vm reporting / interfering). Rabbit cardiac structure-function is more amenable to translational work, e.g. to study fibroblast involvement in normal origin & spread of excitation across the heart, in pathological settings such as arrhythmogenicity of post-infarct scars (a leading causes of sudden death), or as a determinant of therapeutic outcomes such as in healing of atrial ablation lines (interfering with a key interventions to treat atrial fibrillation).
The final ‘blue-skies’ study will assess whether modulation of cardiac activity, from ‘tuning’ of biological pacemaker rates to ‘unpinning’ / termination of re-entrant excitation waves, can be achieved by targeting not myocytes, but fibroblasts.
The study integrates basic-science-driven discovery research into mechanisms and dynamics of biophysical myocyte-fibroblast interactions, generation of novel transgenic models useful for a broad range of studies, and elucidation of conceptually new approaches to heart rhythm management.
Max ERC Funding
2 498 612 €
Duration
Start date: 2013-07-01, End date: 2019-06-30
Project acronym Hallmarks-to-Therapy
Project Intersecting hallmarks of cancer: mechanisms of and interplay between invasion and angiogenesis, guiding new strategies for cancer therapy
Researcher (PI) Douglas Hanahan
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary Acquisition of the hallmark capability for invasion and in turn metastasis is for most human cancers the defining event in progression to life threatening disease. Its determinants are remarkably complex. Genetically engineered mice can model human cancers, with tumors arising in specific organs, reflecting onco-genomic and histopathological features of particular tumor types. This project will use four mouse models to characterize newly implicated determinants of invasive tumor growth. We have observed that genetic polymorphisms can govern predisposition to invasive cancer. Additionally, therapeutic targeting of another hallmark capability – tumor angiogenesis – has revealed adaptive resistance, whereby late-stage tumors, faced with the inability to grow en masse supported by angiogenesis, switch instead to grow diffusively, by invading adjacent tissue; this phenomenon may underlay the limited benefit seen with anti-angiogenic therapies in the clinic. There are three interconnected goals:
(1) Polymorphic regulation of tumor invasion. We will investigate the mechanisms and functional importance of candidate genes resident within a genetic modifier locus on mouse Chr 17 that can alternatively suppress or facilitate invasive tumor growth dependent on constitutional genetic background.
(2) Adaptive induction of invasion. We will elucidate the determinants of the invasive growth capability that is induced in response to potent inhibition of angiogenesis.
(3) Testing mechanism-based therapeutic co-targeting of the capabilities for invasion and angiogenesis.
We will use functional genetic, genomic profiling, and pharmacological approaches to assess these two new modes of regulating invasive growth, and then apply the knowledge in preclinical trials aiming to lay the groundwork for future clinical trials in which these intersecting hallmark capabilities are coordinately disrupted, with promise for more enduring therapeutic responses and benefit to cancer patients.
Summary
Acquisition of the hallmark capability for invasion and in turn metastasis is for most human cancers the defining event in progression to life threatening disease. Its determinants are remarkably complex. Genetically engineered mice can model human cancers, with tumors arising in specific organs, reflecting onco-genomic and histopathological features of particular tumor types. This project will use four mouse models to characterize newly implicated determinants of invasive tumor growth. We have observed that genetic polymorphisms can govern predisposition to invasive cancer. Additionally, therapeutic targeting of another hallmark capability – tumor angiogenesis – has revealed adaptive resistance, whereby late-stage tumors, faced with the inability to grow en masse supported by angiogenesis, switch instead to grow diffusively, by invading adjacent tissue; this phenomenon may underlay the limited benefit seen with anti-angiogenic therapies in the clinic. There are three interconnected goals:
(1) Polymorphic regulation of tumor invasion. We will investigate the mechanisms and functional importance of candidate genes resident within a genetic modifier locus on mouse Chr 17 that can alternatively suppress or facilitate invasive tumor growth dependent on constitutional genetic background.
(2) Adaptive induction of invasion. We will elucidate the determinants of the invasive growth capability that is induced in response to potent inhibition of angiogenesis.
(3) Testing mechanism-based therapeutic co-targeting of the capabilities for invasion and angiogenesis.
We will use functional genetic, genomic profiling, and pharmacological approaches to assess these two new modes of regulating invasive growth, and then apply the knowledge in preclinical trials aiming to lay the groundwork for future clinical trials in which these intersecting hallmark capabilities are coordinately disrupted, with promise for more enduring therapeutic responses and benefit to cancer patients.
Max ERC Funding
2 500 000 €
Duration
Start date: 2013-09-01, End date: 2018-08-31
Project acronym IMMUNODEATH
Project Immunogenic cell death in anticancer therapy
Researcher (PI) Guido Peter Krömer
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary We advocate the hypothesis that successful chemotherapeutics can induce a type of tumor cell stress and death that is immunogenic, meaning that the patient’s dying cancer cells serve as a vaccine that stimulates a specific antitumor immune response, which in turn can control (and sometimes even eradicate) residual cancer cells. This is a highly original – and necessarily controversial – “breakthrough” concept since it challenges previous belief that anticancer chemotherapies act solely on the tumor cells, without any significant involvement of the host immune system. Cell death is usually non-immunogenic, and only a small minority of chemotherapeutic agents can induce immunogenic cell death, which - in contrast to classical apoptosis - is preceded by two types of pre-mortem stress, autophagy (which is required for cellular ATP release, an obligatory signal of immunogenicity) and endoplasmic reticulum (ER) stress (which is required for calreticulin [CRT] exposure at the cell surface, another obligatory signal of immunogenicity). Here, we will explore the hypothesis that cancer cell death is only immunogenic if the two pathways of pre-mortem stress, autophagy and ER stress, are simultaneously activated. Thus, we aim at “decoding” the anticancer drug-induced cellular pathways that regulate the immunogenicity of cell death. For this, we will trigger cancer cell death preceded by one or the two types of pre-mortem stress in a “synthetic system” (by genetic manipulation involving inducible transgenes in cancer cells and mice) or by means of selected pharmacological compounds in multiple in vitro and in vivo cancer models, as we monitor the immune-dependent therapeutic response. Moreover, we will investigate the functional links between autophagy, ER stress and immunogenic signaling. Finally, we will explore the translational relevance of these findings on human cancers.
Summary
We advocate the hypothesis that successful chemotherapeutics can induce a type of tumor cell stress and death that is immunogenic, meaning that the patient’s dying cancer cells serve as a vaccine that stimulates a specific antitumor immune response, which in turn can control (and sometimes even eradicate) residual cancer cells. This is a highly original – and necessarily controversial – “breakthrough” concept since it challenges previous belief that anticancer chemotherapies act solely on the tumor cells, without any significant involvement of the host immune system. Cell death is usually non-immunogenic, and only a small minority of chemotherapeutic agents can induce immunogenic cell death, which - in contrast to classical apoptosis - is preceded by two types of pre-mortem stress, autophagy (which is required for cellular ATP release, an obligatory signal of immunogenicity) and endoplasmic reticulum (ER) stress (which is required for calreticulin [CRT] exposure at the cell surface, another obligatory signal of immunogenicity). Here, we will explore the hypothesis that cancer cell death is only immunogenic if the two pathways of pre-mortem stress, autophagy and ER stress, are simultaneously activated. Thus, we aim at “decoding” the anticancer drug-induced cellular pathways that regulate the immunogenicity of cell death. For this, we will trigger cancer cell death preceded by one or the two types of pre-mortem stress in a “synthetic system” (by genetic manipulation involving inducible transgenes in cancer cells and mice) or by means of selected pharmacological compounds in multiple in vitro and in vivo cancer models, as we monitor the immune-dependent therapeutic response. Moreover, we will investigate the functional links between autophagy, ER stress and immunogenic signaling. Finally, we will explore the translational relevance of these findings on human cancers.
Max ERC Funding
2 500 000 €
Duration
Start date: 2013-04-01, End date: 2018-03-31
Project acronym KATP-DIABETES
Project ATP-sensitive potassium channels: from atomic structure to human disease
Researcher (PI) Frances Mary Ashcroft
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary We are currently experiencing a fast-growing diabetes pandemic. Both type 2 diabetes and rare monogenic forms of diabetes, such as neonatal diabetes, are characterised by impaired insulin secretion. This project seeks to resolve the fundamental mechanisms underlying insulin secretion and its failure in diabetes. We have shown that activating mutations in the ATP-sensitive potassium (KATP) channel cause neonatal diabetes, which has enabled children with this disease to switch from insulin injections to oral sulphonylurea drugs (which block their open KATP channels and stimulate insulin release). The most severe mutations also cause neurological symptoms that, for unknown reasons, are less well treated by sulphonylureas. We aim to: obtain a detailed mechanistic understanding of how nucleotides and drugs regulate KATP channel activity by combining state-of-the-art structural and functional approaches; define how drug therapy affects glucose homeostasis in neonatal diabetes; and explore how activating KATP channel mutations affect glucagon release from pancreatic alpha-cells. We will also investigate how severe KATP channel mutations cause neurological symptoms (such as developmental delay, reduced sensitivity to general anaesthetics and impaired eye movements) and determine how these might be alleviated by drug therapy. While underpinned by my previous work, this project takes my research in new directions, including structural analysis of eukaryotic membrane proteins, stimulus-secretion coupling in other types of islet cell, and neurological studies in humans as well as animal models. It involves a broad multidisciplinary approach, addresses questions of fundamental scientific importance, and has a strong translational element. We expect our studies will be of direct benefit to patients with neonatal or type 2 diabetes.
Summary
We are currently experiencing a fast-growing diabetes pandemic. Both type 2 diabetes and rare monogenic forms of diabetes, such as neonatal diabetes, are characterised by impaired insulin secretion. This project seeks to resolve the fundamental mechanisms underlying insulin secretion and its failure in diabetes. We have shown that activating mutations in the ATP-sensitive potassium (KATP) channel cause neonatal diabetes, which has enabled children with this disease to switch from insulin injections to oral sulphonylurea drugs (which block their open KATP channels and stimulate insulin release). The most severe mutations also cause neurological symptoms that, for unknown reasons, are less well treated by sulphonylureas. We aim to: obtain a detailed mechanistic understanding of how nucleotides and drugs regulate KATP channel activity by combining state-of-the-art structural and functional approaches; define how drug therapy affects glucose homeostasis in neonatal diabetes; and explore how activating KATP channel mutations affect glucagon release from pancreatic alpha-cells. We will also investigate how severe KATP channel mutations cause neurological symptoms (such as developmental delay, reduced sensitivity to general anaesthetics and impaired eye movements) and determine how these might be alleviated by drug therapy. While underpinned by my previous work, this project takes my research in new directions, including structural analysis of eukaryotic membrane proteins, stimulus-secretion coupling in other types of islet cell, and neurological studies in humans as well as animal models. It involves a broad multidisciplinary approach, addresses questions of fundamental scientific importance, and has a strong translational element. We expect our studies will be of direct benefit to patients with neonatal or type 2 diabetes.
Max ERC Funding
2 478 420 €
Duration
Start date: 2013-09-01, End date: 2018-08-31
Project acronym LOCATE
Project "Locomotion, hunting and habitat utilisation among large African carnivores and their prey"
Researcher (PI) Alan Martin Wilson
Host Institution (HI) THE ROYAL VETERINARY COLLEGE
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary "I propose to make the first detailed measurements of the mechanics and energetic cost of locomotor activity including hunting of five large terrestrial carnivore species and their five predominant prey on the southern African savannah. We will refine and use our own innovative design of dynamically responsive tracking collar with high accuracy GPS, accelerometers, gyroscopes, and solar charged batteries to capture round the clock activity, manoeuvring and agility. We will use a geopointing camera gimble on aircraft and UAV to track collared animals and record locomotion of adjacent uncollared animals to obtain high resolution aerial video of hunting. Hunts will be overlaid on a terrain and vegetation map generated using full waveform LiDAR laser scanning and aerial photography to understand the impact of vegetation type, density and surface profile (camber and incline) on locomotion and hunt outcome. We will make detailed measurements of musculoskeletal anatomy and muscle physiology to determine tradeoffs between power and economy for each group and the extent to which hunt performance and outcome can be simply attributed to musculoskeletal physiology and fatigue in the different species.
The technological innovation and integration, its application to wild animals and the massive potential for its application in field biology is all ground breaking. This would be the first investigation of hunting dynamics where every hunt, day and night of a predator is captured and analysed along with prey dynamics (in a subset) to understand what environmental factors influence outcome. It will be the first study to evaluate the extreme dynamics of highly motivated non-domestic species, their anatomy and muscle physiology and the locomotor determinants of successful and unsuccessful hunts. These data and the detailed tracking data will enable studies of terrain utilisation, intra- and inter-species conflict and the impact of vegetation change on species success and survival."
Summary
"I propose to make the first detailed measurements of the mechanics and energetic cost of locomotor activity including hunting of five large terrestrial carnivore species and their five predominant prey on the southern African savannah. We will refine and use our own innovative design of dynamically responsive tracking collar with high accuracy GPS, accelerometers, gyroscopes, and solar charged batteries to capture round the clock activity, manoeuvring and agility. We will use a geopointing camera gimble on aircraft and UAV to track collared animals and record locomotion of adjacent uncollared animals to obtain high resolution aerial video of hunting. Hunts will be overlaid on a terrain and vegetation map generated using full waveform LiDAR laser scanning and aerial photography to understand the impact of vegetation type, density and surface profile (camber and incline) on locomotion and hunt outcome. We will make detailed measurements of musculoskeletal anatomy and muscle physiology to determine tradeoffs between power and economy for each group and the extent to which hunt performance and outcome can be simply attributed to musculoskeletal physiology and fatigue in the different species.
The technological innovation and integration, its application to wild animals and the massive potential for its application in field biology is all ground breaking. This would be the first investigation of hunting dynamics where every hunt, day and night of a predator is captured and analysed along with prey dynamics (in a subset) to understand what environmental factors influence outcome. It will be the first study to evaluate the extreme dynamics of highly motivated non-domestic species, their anatomy and muscle physiology and the locomotor determinants of successful and unsuccessful hunts. These data and the detailed tracking data will enable studies of terrain utilisation, intra- and inter-species conflict and the impact of vegetation change on species success and survival."
Max ERC Funding
3 079 643 €
Duration
Start date: 2013-06-01, End date: 2018-05-31
Project acronym LSD1
Project The lysine-specific demethylase1 (LSD1) in physiology and pathology
Researcher (PI) Roland Schuele
Host Institution (HI) UNIVERSITAETSKLINIKUM FREIBURG
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary "The identification of the first histone demethylase lysine-specific demethylase 1 (LSD1) established not only the concept of reversible histone methylation in epigenetic regulation but also translated this fundamentally novel biological observation into understanding the molecular mechanisms regulation stemness, differentiation, proliferation, and pathological growth. To unravel in an unbiased and comprehensive manner the biological function of LSD1 in physiology and pathology, we developed LSD1-deficient and LSD1-transgenic mouse models. LSD1-transgenic animals develop prostate tumours demonstrating that increased expression of LSD1 suffices for oncogenic growth in vivo. In addition, LSD1-transgenic animals exhibit a metabolic shift towards overt obesity in adulthood. LSD1-deficiency causes early embryonic lethality around day 7.5 of development. However, deletion of LSD1 is not essential for the development of the embryo proper until the onset of gastrulation, suggesting that the early embryonic lethality is caused by trophoblast defects. Indeed, our data demonstrate that LSD1 is crucial for maintaining trophoblast stem cells in their niche and required for the specification of trophoblast stem cell fate during initial steps of differentiation. To identify the underlying mechanisms that allow LSD1 to control a wide range of biological systems such as trophoblast stem cell fate in the early embryo, obesity, and prostate tumourigenesis in the adult, we propose to a) identify LSD1-associated protein complexes and b) LSD1 target genes establishing these phenotypes in the mouse. In addition, we shall uncover c) signalling pathways that modify LSD1 in these phenotypes allowing us to explore the therapeutic potential of targeting these signalling pathways."
Summary
"The identification of the first histone demethylase lysine-specific demethylase 1 (LSD1) established not only the concept of reversible histone methylation in epigenetic regulation but also translated this fundamentally novel biological observation into understanding the molecular mechanisms regulation stemness, differentiation, proliferation, and pathological growth. To unravel in an unbiased and comprehensive manner the biological function of LSD1 in physiology and pathology, we developed LSD1-deficient and LSD1-transgenic mouse models. LSD1-transgenic animals develop prostate tumours demonstrating that increased expression of LSD1 suffices for oncogenic growth in vivo. In addition, LSD1-transgenic animals exhibit a metabolic shift towards overt obesity in adulthood. LSD1-deficiency causes early embryonic lethality around day 7.5 of development. However, deletion of LSD1 is not essential for the development of the embryo proper until the onset of gastrulation, suggesting that the early embryonic lethality is caused by trophoblast defects. Indeed, our data demonstrate that LSD1 is crucial for maintaining trophoblast stem cells in their niche and required for the specification of trophoblast stem cell fate during initial steps of differentiation. To identify the underlying mechanisms that allow LSD1 to control a wide range of biological systems such as trophoblast stem cell fate in the early embryo, obesity, and prostate tumourigenesis in the adult, we propose to a) identify LSD1-associated protein complexes and b) LSD1 target genes establishing these phenotypes in the mouse. In addition, we shall uncover c) signalling pathways that modify LSD1 in these phenotypes allowing us to explore the therapeutic potential of targeting these signalling pathways."
Max ERC Funding
2 488 800 €
Duration
Start date: 2013-04-01, End date: 2018-03-31
Project acronym LYMPHIMMUNE
Project Flow in the tumor microenvironment: Linking mechanobiology with immunology
Researcher (PI) Melody Ann Swartz
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary Tumors often engage the lymphatic system to invade and metastasize. The tumor-draining lymph node (dLN) may be an immune privileged site that protects the tumor from host immunity, and lymph flow draining tumors is often increased, enhancing communication between the tumor and the sentinel node. In addition to increasing transport of tumor antigens and regulatory cytokines to the lymph node, increased lymph flow in the tumor margin causes mechanical stress-induced changes in stromal cells that stiffen the matrix and alter the immune microenvironment of the tumor. In this proposed project, we will investigate the interplay between lymphatic drainage and flow-induced mechanotransduction in the tumor stroma that may synergize to promote tumor immune escape by appropriating lymphatic mechanisms of peripheral tolerance. We will address the hypothesis that lymphatic drainage and flow-induced mechanotransduction in the tumor stroma synergistically promote tumor immune escape by altering the immune microenvironment, and that targeting lymphatic drainage from the tumor may represent a new avenue for tumor immunotherapy. For the latter, we will develop strategies to limit or block lymphatic flow in the tumor microenvironment and characterize their ability to improve the efficacy of tumor immunotherapy by dampening local immunosuppression in the tumor stroma and tumor-draining lymph node (dLN). We will combine in vivo mouse models and intravital imaging with engineered in vitro microenvironments and nanoparticle-based targeting strategies in three broad aims designed to constitute several PhD and postdoctoral projects.
Summary
Tumors often engage the lymphatic system to invade and metastasize. The tumor-draining lymph node (dLN) may be an immune privileged site that protects the tumor from host immunity, and lymph flow draining tumors is often increased, enhancing communication between the tumor and the sentinel node. In addition to increasing transport of tumor antigens and regulatory cytokines to the lymph node, increased lymph flow in the tumor margin causes mechanical stress-induced changes in stromal cells that stiffen the matrix and alter the immune microenvironment of the tumor. In this proposed project, we will investigate the interplay between lymphatic drainage and flow-induced mechanotransduction in the tumor stroma that may synergize to promote tumor immune escape by appropriating lymphatic mechanisms of peripheral tolerance. We will address the hypothesis that lymphatic drainage and flow-induced mechanotransduction in the tumor stroma synergistically promote tumor immune escape by altering the immune microenvironment, and that targeting lymphatic drainage from the tumor may represent a new avenue for tumor immunotherapy. For the latter, we will develop strategies to limit or block lymphatic flow in the tumor microenvironment and characterize their ability to improve the efficacy of tumor immunotherapy by dampening local immunosuppression in the tumor stroma and tumor-draining lymph node (dLN). We will combine in vivo mouse models and intravital imaging with engineered in vitro microenvironments and nanoparticle-based targeting strategies in three broad aims designed to constitute several PhD and postdoctoral projects.
Max ERC Funding
2 217 582 €
Duration
Start date: 2013-05-01, End date: 2016-12-31
Project acronym MITCARE
Project Mitochondrial Medicine: developing treatments of OXPHOS-defects in recombinant mammalian models
Researcher (PI) Massimo Zeviani
Host Institution (HI) MEDICAL RESEARCH COUNCIL
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary Mitochondria are the major source of ATP, synthesized by the mitochondrial respiratory chain (MRC) through the process of oxidative phosphorylation. ATP deficiency leads to cellular dysfunction and ultimately death. In mammals, 13 mitochondrial DNA (mtDNA)-encoded subunits interact with over 70 nuclear-encoded subunits to form four of the five MRC complexes. Many additional factors are essential for the regulation of MRC activity, and the maintenance and expression of mtDNA. As a result, genetic defects affecting either genome can compromise ATP synthesis and cause human disease. There is no effective treatment for mitochondrial disorders. Major hurdles to this achievement include (i) the still incomplete molecular definition of mitochondrial disease; (ii) the poorly understood function of many disease gene products, (iii) the difficulty to rationally manipulate the complex biochemical and genetic systems underpinning mitochondrial bioenergetics.
The ultimate scope of MitCare is to develop effective therapy in mitochondrial medicine. MitCare will implement three Workpackages (WP). WP1 will test the effects of pharmacological stimulation of mitochondrial biogenesis in mouse disease models. WP2 will test the effects of Adeno-Associated Viral (AAV)- and lentiviral-mediated delivery of therapeutic genes, in mouse models and human mutant cells, respectively. Since the clinical features of human disorders often fail to be faithfully replicated in mice, WP3 will implement the creation of a mitochondrial disease model in the pig, whose proximity to humans is much closer than mice. The Surf1 gene, encoding an assembly factor of complex IV, will be disrupted by zincfinger nuclease technology in swine fibroblasts, which will then serve to clone a Surf1 knockout pig by somatic cell nuclear transfer. “Mitopigs” will be used to test the direct transferability of experimental treatments from suitable mammalian models to the clinics.
Summary
Mitochondria are the major source of ATP, synthesized by the mitochondrial respiratory chain (MRC) through the process of oxidative phosphorylation. ATP deficiency leads to cellular dysfunction and ultimately death. In mammals, 13 mitochondrial DNA (mtDNA)-encoded subunits interact with over 70 nuclear-encoded subunits to form four of the five MRC complexes. Many additional factors are essential for the regulation of MRC activity, and the maintenance and expression of mtDNA. As a result, genetic defects affecting either genome can compromise ATP synthesis and cause human disease. There is no effective treatment for mitochondrial disorders. Major hurdles to this achievement include (i) the still incomplete molecular definition of mitochondrial disease; (ii) the poorly understood function of many disease gene products, (iii) the difficulty to rationally manipulate the complex biochemical and genetic systems underpinning mitochondrial bioenergetics.
The ultimate scope of MitCare is to develop effective therapy in mitochondrial medicine. MitCare will implement three Workpackages (WP). WP1 will test the effects of pharmacological stimulation of mitochondrial biogenesis in mouse disease models. WP2 will test the effects of Adeno-Associated Viral (AAV)- and lentiviral-mediated delivery of therapeutic genes, in mouse models and human mutant cells, respectively. Since the clinical features of human disorders often fail to be faithfully replicated in mice, WP3 will implement the creation of a mitochondrial disease model in the pig, whose proximity to humans is much closer than mice. The Surf1 gene, encoding an assembly factor of complex IV, will be disrupted by zincfinger nuclease technology in swine fibroblasts, which will then serve to clone a Surf1 knockout pig by somatic cell nuclear transfer. “Mitopigs” will be used to test the direct transferability of experimental treatments from suitable mammalian models to the clinics.
Max ERC Funding
2 500 000 €
Duration
Start date: 2013-07-01, End date: 2018-06-30
Project acronym ONCOTREAT
Project Identification of Novel Targeted Therapies for Renal Cancer
Researcher (PI) Eamonn Richard Maher
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary "Overall, kidney cancers are the eighth most common cancer and the incidence of the most common form (renal cell carcinoma, RCC) has been increasing steadily over the past 30 years. If detected early, surgical removal of RCC can be curative but the prognosis for metastatic disease is very poor. RCC is resistant to conventional therapy and recently introduced targeted therapies form the mainstay of treatment for metastatic disease. The rationale for the use of targeted therapies (e.g. antiangiogenic tyrosine kinase inhibitors) in RCC was derived from functional investigations of the mechanism of tumourigenesis in the rare inherited RCC syndrome von Hippel-Lindau disease. Whilst currently available targeted therapies can extend progression free survival in advanced RCC they are not curative and better treatments are urgently required. Large scale genomic studies of RCC are in progress and will greatly enhance current knowledge of the molecular pathology of RCC. However, experience from other cancers suggests that the results of genomic analyses of cancer are complex and identifying the key “gatekeeper genes” is frequently challenging. ONCOTREAT is based on the hypothesis that (a) the identification of the genetic basis of inherited forms of RCC will highlight those genes and pathways that are critical for tumourigenesis and (b) that selective targeting of cells deficient in inherited RCC gene function will enable advances in the treatment of inherited and sporadic RCC.
The objectives of ONCOTREAT are to:
1. Identify novel inherited RCC genes
2. Generate and characterise human cell line models for inherited RCC genes
3. Identify candidate therapeutic agents that, in in vitro studies, selectively target human cell line models of inherited RCC genes dysfunction
4. Evaluate candidate therapeutic agents identified from in vitro studies in in vivo investigations to identify agents that target cancers deficient in inherited RCC gatekeeper genes."
Summary
"Overall, kidney cancers are the eighth most common cancer and the incidence of the most common form (renal cell carcinoma, RCC) has been increasing steadily over the past 30 years. If detected early, surgical removal of RCC can be curative but the prognosis for metastatic disease is very poor. RCC is resistant to conventional therapy and recently introduced targeted therapies form the mainstay of treatment for metastatic disease. The rationale for the use of targeted therapies (e.g. antiangiogenic tyrosine kinase inhibitors) in RCC was derived from functional investigations of the mechanism of tumourigenesis in the rare inherited RCC syndrome von Hippel-Lindau disease. Whilst currently available targeted therapies can extend progression free survival in advanced RCC they are not curative and better treatments are urgently required. Large scale genomic studies of RCC are in progress and will greatly enhance current knowledge of the molecular pathology of RCC. However, experience from other cancers suggests that the results of genomic analyses of cancer are complex and identifying the key “gatekeeper genes” is frequently challenging. ONCOTREAT is based on the hypothesis that (a) the identification of the genetic basis of inherited forms of RCC will highlight those genes and pathways that are critical for tumourigenesis and (b) that selective targeting of cells deficient in inherited RCC gene function will enable advances in the treatment of inherited and sporadic RCC.
The objectives of ONCOTREAT are to:
1. Identify novel inherited RCC genes
2. Generate and characterise human cell line models for inherited RCC genes
3. Identify candidate therapeutic agents that, in in vitro studies, selectively target human cell line models of inherited RCC genes dysfunction
4. Evaluate candidate therapeutic agents identified from in vitro studies in in vivo investigations to identify agents that target cancers deficient in inherited RCC gatekeeper genes."
Max ERC Funding
2 247 890 €
Duration
Start date: 2013-09-01, End date: 2018-08-31
Project acronym RASTARGET
Project Targeting RAS oncogene addiction
Researcher (PI) David Julian Downward
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary Lung cancer is the most common type of malignant tumour worldwide and the leading cause of cancer-related death (335,000 deaths per year in Europe). The KRAS oncogene is frequently activated by point mutation in human lung cancer and mutations in the RAS family oncogenes are responsible for driving some 20% of all human malignancies. Most cell lines from RAS mutant tumours remain “oncogene addicted” to continued RAS function. There is therefore a pressing need to develop cancer therapies that target RAS.
To date it has proven impossible to target the RAS proteins directly and it is unclear whether combined targeting of downstream pathways that RAS controls will prove effective. We have previously probed the unique vulnerabilities of RAS mutant cancer cells using synthetic lethal genome-wide screening approaches. This has led to the identification of a transcriptional programme controlled by GATA2 that is selectively essential for RAS mutant lung cancer cell survival. Deletion of GATA2 leads to dramatic regression of RAS induced in lung cancer in mouse models. Although GATA2 itself is likely to be undruggable, combined suppression of two GATA2 regulated pathways, ROCK and the proteasome, with clinically approved inhibitors causes marked tumour clearance.
We propose to investigate the ability of these promising targeting strategies to impact on various RAS induced cancers and also to investigate mechanistic aspects of this dependency on GATA2 function. We will test the effect of GATA2 deletion or ROCK/proteasome combination therapy on RAS mutant tumour maintenance in the setting of p53 loss, both in lung and pancreatic cancer. In addition, we will determine the mechanisms involved in the dependency of RAS mutant cancers on these pathways in vivo, including investigating effects on the interaction of the tumour with host tissues, with a view to finding improved means of targeting these tumours and avoiding the development of resistance to these therapies.
Summary
Lung cancer is the most common type of malignant tumour worldwide and the leading cause of cancer-related death (335,000 deaths per year in Europe). The KRAS oncogene is frequently activated by point mutation in human lung cancer and mutations in the RAS family oncogenes are responsible for driving some 20% of all human malignancies. Most cell lines from RAS mutant tumours remain “oncogene addicted” to continued RAS function. There is therefore a pressing need to develop cancer therapies that target RAS.
To date it has proven impossible to target the RAS proteins directly and it is unclear whether combined targeting of downstream pathways that RAS controls will prove effective. We have previously probed the unique vulnerabilities of RAS mutant cancer cells using synthetic lethal genome-wide screening approaches. This has led to the identification of a transcriptional programme controlled by GATA2 that is selectively essential for RAS mutant lung cancer cell survival. Deletion of GATA2 leads to dramatic regression of RAS induced in lung cancer in mouse models. Although GATA2 itself is likely to be undruggable, combined suppression of two GATA2 regulated pathways, ROCK and the proteasome, with clinically approved inhibitors causes marked tumour clearance.
We propose to investigate the ability of these promising targeting strategies to impact on various RAS induced cancers and also to investigate mechanistic aspects of this dependency on GATA2 function. We will test the effect of GATA2 deletion or ROCK/proteasome combination therapy on RAS mutant tumour maintenance in the setting of p53 loss, both in lung and pancreatic cancer. In addition, we will determine the mechanisms involved in the dependency of RAS mutant cancers on these pathways in vivo, including investigating effects on the interaction of the tumour with host tissues, with a view to finding improved means of targeting these tumours and avoiding the development of resistance to these therapies.
Max ERC Funding
2 496 221 €
Duration
Start date: 2013-05-01, End date: 2019-04-30
Project acronym StemCellGerontoGenes
Project Longevity and aging associated genes that control self-renewal and function of adult stem cells during aging
Researcher (PI) Karl Lenhard Rudolph
Host Institution (HI) LEIBNIZ-INSTITUT FUR ALTERNSFORSCHUNG - FRITZ-LIPMANN-INSTITUT EV (FLI) LEIBNIZ INSTITUTE ON AGING - FRITZ LIPMANN INSTITUTE EV (FLI)
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary Adult stem cells are essential for the lifelong maintenance and regeneration of various organs and tissues. Experimental and clinical data indicate that the functional capacity of adult stem cells in organ regeneration declines during aging. Molecular mechanisms that cause impairments in stem cell function during aging remain to be delineated. Genetic analyses identified a growing number of genes and genetic loci that are associated with longevity and aging in model organisms and humans. For most of these associations the molecular mechanisms and its functional relevance for mammalian aging remain unknown. In many cases of genetic loci associations, the responsible genes have not even been identified. A bottleneck in our understanding of aging remains to identify functionally relevant genes and molecular mechanisms from this growing list of genetic association with aging. Emerging experimental data indicate that aging/longevity-associated genes influence the functional reserve of adult stem cells. Here, I propose to develop and lead a research program analyzing longevity and aging associated genes and gene loci by reverse genetic approaches. In vivo and ex vivo RNAi will identify genes and molecular mechanisms that affect the function of stem cells in aging mice or genetically engineered mice modeling accelerated accumulation of molecular damages and stem cell dysfunction. Analysis of primary human stem cells from young vs. old donors will delineate whether the identified genes and mechanisms are conserved in humans. Reverse genetic approaches of aging/longevity-associated genes have not been conducted in adult mammalian stem cells. Our group gained significant expertise in analyzing molecular mechanisms of stem cell maintenance and function as well as in conducting RNAi screens in different murine stem cell compartments. Our studies will delineate novel mechanisms of stem cell aging and its implication for defects in organ homeostasis and regeneration during aging.
Summary
Adult stem cells are essential for the lifelong maintenance and regeneration of various organs and tissues. Experimental and clinical data indicate that the functional capacity of adult stem cells in organ regeneration declines during aging. Molecular mechanisms that cause impairments in stem cell function during aging remain to be delineated. Genetic analyses identified a growing number of genes and genetic loci that are associated with longevity and aging in model organisms and humans. For most of these associations the molecular mechanisms and its functional relevance for mammalian aging remain unknown. In many cases of genetic loci associations, the responsible genes have not even been identified. A bottleneck in our understanding of aging remains to identify functionally relevant genes and molecular mechanisms from this growing list of genetic association with aging. Emerging experimental data indicate that aging/longevity-associated genes influence the functional reserve of adult stem cells. Here, I propose to develop and lead a research program analyzing longevity and aging associated genes and gene loci by reverse genetic approaches. In vivo and ex vivo RNAi will identify genes and molecular mechanisms that affect the function of stem cells in aging mice or genetically engineered mice modeling accelerated accumulation of molecular damages and stem cell dysfunction. Analysis of primary human stem cells from young vs. old donors will delineate whether the identified genes and mechanisms are conserved in humans. Reverse genetic approaches of aging/longevity-associated genes have not been conducted in adult mammalian stem cells. Our group gained significant expertise in analyzing molecular mechanisms of stem cell maintenance and function as well as in conducting RNAi screens in different murine stem cell compartments. Our studies will delineate novel mechanisms of stem cell aging and its implication for defects in organ homeostasis and regeneration during aging.
Max ERC Funding
2 498 400 €
Duration
Start date: 2013-07-01, End date: 2018-06-30
Project acronym SYMPHONY
Project Sudden Cardiac Death and Electrical Dyssynchrony Mediated by Purkinje-His Dysfunctional Activity
Researcher (PI) Jean Michel Haissaguerre
Host Institution (HI) UNIVERSITE DE BORDEAUX
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary "Cardiovascular disease is the first cause of mortality in the whole world (WHO 2008), responsible for 700000 deaths each year in Europe; a huge burden on healtcare. Half of this mortality is due to heart failure (HF), which can be caused or further aggravated by electrical dyssynchrony. The other half of cardiac mortality occurs suddenly, essentially due to ventricular tachyarrhythmias.
The main objectives of SYMPHONY are (i) to advance our fundamental understanding in the mechanisms underlying SCD and electrical dyssynchrony in HF, with a strong focus on the specialized ventricular conduction network, and (ii) to improve current preventive, diagnostic and treatment methods for these life-threatening cardiac electrical disorders.
SYMPHONY is a multidisciplinary project that will benefit from a wide array of state-of-the-art methodologies and expertise, both in fundamental and clinical sciences. A large mammalian species, the sheep, will be used for a detailed characterization of the properties of the conduction network in health and disease. Importantly, a limited number of explanted human hearts will be available on which all these techniques will equally be applicable. From our clinical work, SYMPHONY will benefit from cutting edge tools in epicardial and catheter mapping allowing simultaneous mapping of the Purkinje system and ventricular substrate. The gathered data will be fed into large-scale computer models that will allow personalized investigations into the mechanisms of SCD and electrical dyssynchrony.
SYMPHONY has a significant potential for industrial valorisation and is likely to introduce new targets for interventions, and new methods for risk stratification and prevention. Therefore we can affirm that this unprecedented, comprehensive and translational project will lead to major advances in scientific knowledge, will have a significant impact on healthcare budgets and, most importantly, will dramatically improve quality of life and patient care."
Summary
"Cardiovascular disease is the first cause of mortality in the whole world (WHO 2008), responsible for 700000 deaths each year in Europe; a huge burden on healtcare. Half of this mortality is due to heart failure (HF), which can be caused or further aggravated by electrical dyssynchrony. The other half of cardiac mortality occurs suddenly, essentially due to ventricular tachyarrhythmias.
The main objectives of SYMPHONY are (i) to advance our fundamental understanding in the mechanisms underlying SCD and electrical dyssynchrony in HF, with a strong focus on the specialized ventricular conduction network, and (ii) to improve current preventive, diagnostic and treatment methods for these life-threatening cardiac electrical disorders.
SYMPHONY is a multidisciplinary project that will benefit from a wide array of state-of-the-art methodologies and expertise, both in fundamental and clinical sciences. A large mammalian species, the sheep, will be used for a detailed characterization of the properties of the conduction network in health and disease. Importantly, a limited number of explanted human hearts will be available on which all these techniques will equally be applicable. From our clinical work, SYMPHONY will benefit from cutting edge tools in epicardial and catheter mapping allowing simultaneous mapping of the Purkinje system and ventricular substrate. The gathered data will be fed into large-scale computer models that will allow personalized investigations into the mechanisms of SCD and electrical dyssynchrony.
SYMPHONY has a significant potential for industrial valorisation and is likely to introduce new targets for interventions, and new methods for risk stratification and prevention. Therefore we can affirm that this unprecedented, comprehensive and translational project will lead to major advances in scientific knowledge, will have a significant impact on healthcare budgets and, most importantly, will dramatically improve quality of life and patient care."
Max ERC Funding
2 489 646 €
Duration
Start date: 2013-09-01, End date: 2018-08-31
Project acronym VASNICHE
Project The vascular stem cell niche and the neurovascular unit
Researcher (PI) Eliahu Keshet
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary Recent evidence suggests that VEGF and the vasculature play multiple roles in organ homeostasis, functions extending far beyond their traditional roles in tissue perfusion. The proposed study represents a vascular-centred approach to the neurovascular unit thriving to gain further insights on the many ways by which blood vessels may affect proper brain functioning. Major focus is on the vascular stem cell niche, i.e. the contention that blood vessels are a key component of adult stem cell niches, including a niche securing proper function of neuronal stem cells (NSCs). Further insights on the niche are also critical for contemplated implementation of stem-cell based therapy. In this multidisciplinary study combining the fields of vascular biology, neurobiology, stem cell biology, and aging research, we harness unique transgenic methodologies to conditionally manipulate (via VEGF) the vasculature within the stem cell niches. We provide a first compelling proof that blood vessels at the niche indeed control stem cells properties and behaviour, evidenced by showing that mere expansion of the niche vasculature and independently of VEGF) increases dramatically adult hippocampal neurogenesis, a process known to be associated with improved cognitive performance. We will determine what aspects of stem cell biology are controlled by juxtaposed, directly contacting blood vessels and will identify signalling systems mediating the vascular/stem cell cross-talk.
Adult neurogenesis is known to rapidly decline with age and ways to sustain the process are highly desired. We hypothesize and, in fact, provide initial evidence that expanding and 'rejuvenating' the niche vasculature can override the natural age-dependent decline of adult neurogenesis. Proposed experiments will extend this exciting finding and thrive to uncover the underlying mechanisms.
Summary
Recent evidence suggests that VEGF and the vasculature play multiple roles in organ homeostasis, functions extending far beyond their traditional roles in tissue perfusion. The proposed study represents a vascular-centred approach to the neurovascular unit thriving to gain further insights on the many ways by which blood vessels may affect proper brain functioning. Major focus is on the vascular stem cell niche, i.e. the contention that blood vessels are a key component of adult stem cell niches, including a niche securing proper function of neuronal stem cells (NSCs). Further insights on the niche are also critical for contemplated implementation of stem-cell based therapy. In this multidisciplinary study combining the fields of vascular biology, neurobiology, stem cell biology, and aging research, we harness unique transgenic methodologies to conditionally manipulate (via VEGF) the vasculature within the stem cell niches. We provide a first compelling proof that blood vessels at the niche indeed control stem cells properties and behaviour, evidenced by showing that mere expansion of the niche vasculature and independently of VEGF) increases dramatically adult hippocampal neurogenesis, a process known to be associated with improved cognitive performance. We will determine what aspects of stem cell biology are controlled by juxtaposed, directly contacting blood vessels and will identify signalling systems mediating the vascular/stem cell cross-talk.
Adult neurogenesis is known to rapidly decline with age and ways to sustain the process are highly desired. We hypothesize and, in fact, provide initial evidence that expanding and 'rejuvenating' the niche vasculature can override the natural age-dependent decline of adult neurogenesis. Proposed experiments will extend this exciting finding and thrive to uncover the underlying mechanisms.
Max ERC Funding
2 499 980 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym WAYS
Project Role of Liver Estrogen Receptor in female Energy Metabolism, Reproduction and Aging: What About Your Liver Sexual Functions?
Researcher (PI) Adriana Caterina Elvira Maggi
Host Institution (HI) UNIVERSITA DEGLI STUDI DI MILANO
Call Details Advanced Grant (AdG), LS4, ERC-2012-ADG_20120314
Summary In mammals, the liver is the peripheral integrator of nutrient availability and energetic needs of the entire organism. We recently demonstrated that dietary amino acids (AA) activate liver Estrogen Receptors (ER) and that, in case of food scarcity, the lowered circulating AA decrease liver ER activity and reduce IGF-1 synthesis with the consequent blockage of the estrous cycle.
Here, we hypothesize that in females liver ERa is also a sensor of the endogenous signalling induced by transitions among reproductive stages and a key organizer for the changes required to adapt energy metabolism to reproductive necessities. Thus, we propose that in mammals liver ERa is regulated by reproductive functions and that, in case of ovary malfunctioning, the altered estrogenic signalling causes metabolic impairment leading to local and perhaps systemic disruption of energy homeostasis.
To demonstrate our theory, we will explore: i) the molecular pathways activating liver ERa and the related ERa transcriptome by genome-wide analytical tools; ii) the hepatic metabolism and the systemic consequences of liver ER pharmacological and genetic manipulations by means of metabolomic technologies; iii) the association between altered signalling on liver ER and the onset of metabolic disorders; iv) the molecular interactions between ER and PPAR activity and the effect of estrogens on liver autophagy.
WAYS research is facilitated by a series of tools such as ER conditional KO, reporter mice, arrays of genes known as target of liver ERa, and others generated by our laboratory in collaboration with EU groups in previous EU programs.
The vision of the liver as a functional unit with reproductive organs constitutes a paradigm shift in our understanding of woman physiology; thus, the full comprehension of liver ERa activity and regulation will be a critical step for the conception of new therapies for several diseases affecting women including the metabolic syndrome or the non-alcoholic steatosis.
Summary
In mammals, the liver is the peripheral integrator of nutrient availability and energetic needs of the entire organism. We recently demonstrated that dietary amino acids (AA) activate liver Estrogen Receptors (ER) and that, in case of food scarcity, the lowered circulating AA decrease liver ER activity and reduce IGF-1 synthesis with the consequent blockage of the estrous cycle.
Here, we hypothesize that in females liver ERa is also a sensor of the endogenous signalling induced by transitions among reproductive stages and a key organizer for the changes required to adapt energy metabolism to reproductive necessities. Thus, we propose that in mammals liver ERa is regulated by reproductive functions and that, in case of ovary malfunctioning, the altered estrogenic signalling causes metabolic impairment leading to local and perhaps systemic disruption of energy homeostasis.
To demonstrate our theory, we will explore: i) the molecular pathways activating liver ERa and the related ERa transcriptome by genome-wide analytical tools; ii) the hepatic metabolism and the systemic consequences of liver ER pharmacological and genetic manipulations by means of metabolomic technologies; iii) the association between altered signalling on liver ER and the onset of metabolic disorders; iv) the molecular interactions between ER and PPAR activity and the effect of estrogens on liver autophagy.
WAYS research is facilitated by a series of tools such as ER conditional KO, reporter mice, arrays of genes known as target of liver ERa, and others generated by our laboratory in collaboration with EU groups in previous EU programs.
The vision of the liver as a functional unit with reproductive organs constitutes a paradigm shift in our understanding of woman physiology; thus, the full comprehension of liver ERa activity and regulation will be a critical step for the conception of new therapies for several diseases affecting women including the metabolic syndrome or the non-alcoholic steatosis.
Max ERC Funding
1 445 381 €
Duration
Start date: 2013-04-01, End date: 2019-03-31
