Project acronym BETATOBETA
Project The molecular basis of pancreatic beta cell replication
Researcher (PI) Yuval Dor
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS4, ERC-2010-StG_20091118
Summary A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size. A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size.
Summary
A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size. A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size.
Max ERC Funding
1 445 000 €
Duration
Start date: 2010-09-01, End date: 2015-08-31
Project acronym CARDIO-IPS
Project Induced Pluripotent stem Cells: A Novel Strategy to Study Inherited Cardiac Disorders
Researcher (PI) Lior Gepstein
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Starting Grant (StG), LS4, ERC-2010-StG_20091118
Summary The study of several genetic disorders is hampered by the lack of suitable in vitro human models. We hypothesize that the generation of patient-specific induced pluripotent stem cells (iPSCs) will allow the development of disease-specific in vitro models; yielding new pathophysiologic insights into several genetic disorders and offering a unique platform to test novel therapeutic strategies. In the current proposal we plan utilize this novel approach to establish human iPSC (hiPSC) lines for the study of a variety of inherited cardiac disorders. The specific disease states that will be studied were chosen to reflect abnormalities in a wide-array of different cardiomyocyte cellular processes.
These include mutations leading to:
(1) abnormal ion channel function (“channelopathies”), such as the long QT and Brugada syndromes;
(2) abnormal intracellular storage of unnecessary material, such as in the glycogen storage disease type IIb (Pompe’s disease); and
(3) abnormalities in cell-to-cell contacts, such as in the case of arrhythmogenic right ventricular cardiomyopathy-dysplasia (ARVC-D). The different hiPSC lines generated will be coaxed to differentiate into the cardiac lineage. Detailed molecular, structural, functional, and pharmacological studies will then be performed to characterize the phenotypic properties of the generated hiPSC-derived cardiomyocytes, with specific emphasis on their molecular, ultrastructural, electrophysiological, and Ca2+ handling properties.
These studies should provide new insights into the pathophysiological mechanisms underlying the different familial arrhythmogenic and cardiomyopathy disorders studied, may allow optimization of patient-specific therapies (personalized medicine), and may facilitate the development of novel therapeutic strategies.
Moreover, the concepts and methodological knowhow developed in the current project could be extended, in the future, to derive human disease-specific cell culture models for a plurality of genetic disorders; enabling translational research ranging from investigation of the most fundamental cellular mechanisms involved in human tissue formation and physiology through disease investigation and the development and testing of novel therapies that could potentially find their way to the bedside
Summary
The study of several genetic disorders is hampered by the lack of suitable in vitro human models. We hypothesize that the generation of patient-specific induced pluripotent stem cells (iPSCs) will allow the development of disease-specific in vitro models; yielding new pathophysiologic insights into several genetic disorders and offering a unique platform to test novel therapeutic strategies. In the current proposal we plan utilize this novel approach to establish human iPSC (hiPSC) lines for the study of a variety of inherited cardiac disorders. The specific disease states that will be studied were chosen to reflect abnormalities in a wide-array of different cardiomyocyte cellular processes.
These include mutations leading to:
(1) abnormal ion channel function (“channelopathies”), such as the long QT and Brugada syndromes;
(2) abnormal intracellular storage of unnecessary material, such as in the glycogen storage disease type IIb (Pompe’s disease); and
(3) abnormalities in cell-to-cell contacts, such as in the case of arrhythmogenic right ventricular cardiomyopathy-dysplasia (ARVC-D). The different hiPSC lines generated will be coaxed to differentiate into the cardiac lineage. Detailed molecular, structural, functional, and pharmacological studies will then be performed to characterize the phenotypic properties of the generated hiPSC-derived cardiomyocytes, with specific emphasis on their molecular, ultrastructural, electrophysiological, and Ca2+ handling properties.
These studies should provide new insights into the pathophysiological mechanisms underlying the different familial arrhythmogenic and cardiomyopathy disorders studied, may allow optimization of patient-specific therapies (personalized medicine), and may facilitate the development of novel therapeutic strategies.
Moreover, the concepts and methodological knowhow developed in the current project could be extended, in the future, to derive human disease-specific cell culture models for a plurality of genetic disorders; enabling translational research ranging from investigation of the most fundamental cellular mechanisms involved in human tissue formation and physiology through disease investigation and the development and testing of novel therapies that could potentially find their way to the bedside
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-03-01, End date: 2016-02-29
Project acronym CHD-IPS
Project Modeling congenital heart disease (CHD) in ISL1+ cardiovascular progenitors from patient-specific iPS cells
Researcher (PI) Karl-Ludwig Laugwitz
Host Institution (HI) KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Call Details Starting Grant (StG), LS4, ERC-2010-StG_20091118
Summary Tetralogy of Fallot (TOF) is the most common congenital heart disease (CHD) occurring 1 in 3000 births. Genetic studies have identified numerous genes that are responsible for inherited and sporadic forms of TOF, most of which encode key molecules that are part of regulatory networks controlling heart development. The identification of two populations of cardiac precursors, one exclusively forming the left ventricle and the second the outflow tract, the right ventricle and the atria, has suggested a new approach to interpret CHDs, in particular in TOF, not as a defect in a specific gene, but rather as a defect in the formation, expansion, and differentiation of defined subsets of embryonic cardiac precursors. The LIM-homeodomain transcription factor ISL1 marks the second population of cardiac progenitors, but little is known about its downstream targets, and how causative genes of CHDs affect cell-fate decisions in the ISL1 lineage. The main goals of this research program are: (1) to decipher the functional role of Isl1 downstream targets identified by a genome-wide ChIP-Seq approach; (2) to generate induced pluripotent stem (iPS) cells from controls and patients affected by severe forms of TOF characterized by defects in heart compartments known to derive from ISL1 cardiac progenitors; (3) to direct these iPS cells to ISL1+ cardiovascular precursors and identify cell-surface makers enabling their antibody-based purification; and (4) to use TOF-iPS-derived ISL1+ progenitors as an unique in vitro model system for deciphering molecular mechanisms that govern the fates and differentiation of this progenitor lineage and determine the pathological phenotype seen in TOF. This work will shed light on the molecular mechanisms of ISL1+ cardiac progenitor lineage specification and will give important new insights into the mechanisms of how alterations in transcriptional and epigenetic programs translate to a distinct structural defect during cardiogenesis.
Summary
Tetralogy of Fallot (TOF) is the most common congenital heart disease (CHD) occurring 1 in 3000 births. Genetic studies have identified numerous genes that are responsible for inherited and sporadic forms of TOF, most of which encode key molecules that are part of regulatory networks controlling heart development. The identification of two populations of cardiac precursors, one exclusively forming the left ventricle and the second the outflow tract, the right ventricle and the atria, has suggested a new approach to interpret CHDs, in particular in TOF, not as a defect in a specific gene, but rather as a defect in the formation, expansion, and differentiation of defined subsets of embryonic cardiac precursors. The LIM-homeodomain transcription factor ISL1 marks the second population of cardiac progenitors, but little is known about its downstream targets, and how causative genes of CHDs affect cell-fate decisions in the ISL1 lineage. The main goals of this research program are: (1) to decipher the functional role of Isl1 downstream targets identified by a genome-wide ChIP-Seq approach; (2) to generate induced pluripotent stem (iPS) cells from controls and patients affected by severe forms of TOF characterized by defects in heart compartments known to derive from ISL1 cardiac progenitors; (3) to direct these iPS cells to ISL1+ cardiovascular precursors and identify cell-surface makers enabling their antibody-based purification; and (4) to use TOF-iPS-derived ISL1+ progenitors as an unique in vitro model system for deciphering molecular mechanisms that govern the fates and differentiation of this progenitor lineage and determine the pathological phenotype seen in TOF. This work will shed light on the molecular mechanisms of ISL1+ cardiac progenitor lineage specification and will give important new insights into the mechanisms of how alterations in transcriptional and epigenetic programs translate to a distinct structural defect during cardiogenesis.
Max ERC Funding
1 499 996 €
Duration
Start date: 2011-03-01, End date: 2017-02-28
Project acronym COMPLEXI&AGING
Project Modulation of mitochondrial complex I as a strategy to increase lifespan and prevent age-related diseases
Researcher (PI) Alberto Sanz Montero
Host Institution (HI) UNIVERSITY OF NEWCASTLE UPON TYNE
Call Details Starting Grant (StG), LS4, ERC-2010-StG_20091118
Summary Nowadays, ageing is one of the main problems in Western society. The increase in the percentage of elderly people serves to strain the Social Security to the point of bankruptcy. The only way to alleviate the suffering caused by age-related degenerative disease is to fully understand the underlying forces which drive ageing and design strategies to delay it. Mitochondria are considered as central modulators of longevity in different species. It has been proposed that free radicals cause the accumulation of oxidative damage and as a result ageing. In accordance with this, production of Reactive Oxygen Species (ROS) by complex I negatively correlates with longevity. However, the overexpression of antioxidants or the reduction of ROS levels does not increase lifespan. These contradictory data can only be reconciled if complex I is modulating longevity through a ROS independent mechanism. We have expressed the alternative internal NADH dehydrogenase 1 (NDI1) from Saccharomyces cerevisiae in Drosophila melanogaster. The expression of NDI1 does not change the level of ROS but increases both the ratio of NAD+/NADH and Drosophila longevity. The main objective of this proposal is to study the mechanisms by which complex I regulates longevity. My general hypothesis is that complex I regulates longevity through a ROS independent mechanism. I propose that complex I controls the cellular levels of NAD+/NADH, keeping their levels at an equilibrium that favours the optimal functioning of the cell. When the ratio is moved towards NADH ageing is promoted, whereas when it is moved towards NAD+ pro-survival pathways are activated. I proposed two specific mechanisms downstream of complex I that promote cellular longevity or senescence: 1) activation of sirtuins, which would increase genome stability and 2) reduction of methylglyoxal generation, which would decrease the accumulation of cellular garbarge .
Summary
Nowadays, ageing is one of the main problems in Western society. The increase in the percentage of elderly people serves to strain the Social Security to the point of bankruptcy. The only way to alleviate the suffering caused by age-related degenerative disease is to fully understand the underlying forces which drive ageing and design strategies to delay it. Mitochondria are considered as central modulators of longevity in different species. It has been proposed that free radicals cause the accumulation of oxidative damage and as a result ageing. In accordance with this, production of Reactive Oxygen Species (ROS) by complex I negatively correlates with longevity. However, the overexpression of antioxidants or the reduction of ROS levels does not increase lifespan. These contradictory data can only be reconciled if complex I is modulating longevity through a ROS independent mechanism. We have expressed the alternative internal NADH dehydrogenase 1 (NDI1) from Saccharomyces cerevisiae in Drosophila melanogaster. The expression of NDI1 does not change the level of ROS but increases both the ratio of NAD+/NADH and Drosophila longevity. The main objective of this proposal is to study the mechanisms by which complex I regulates longevity. My general hypothesis is that complex I regulates longevity through a ROS independent mechanism. I propose that complex I controls the cellular levels of NAD+/NADH, keeping their levels at an equilibrium that favours the optimal functioning of the cell. When the ratio is moved towards NADH ageing is promoted, whereas when it is moved towards NAD+ pro-survival pathways are activated. I proposed two specific mechanisms downstream of complex I that promote cellular longevity or senescence: 1) activation of sirtuins, which would increase genome stability and 2) reduction of methylglyoxal generation, which would decrease the accumulation of cellular garbarge .
Max ERC Funding
1 491 600 €
Duration
Start date: 2011-02-01, End date: 2016-09-30
Project acronym DISSECT
Project Disseminating tumor cells as novel biomarkers: Dissecting the metastatic cascade in cancer patients
Researcher (PI) Klaus Pantel
Host Institution (HI) UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF
Call Details Advanced Grant (AdG), LS4, ERC-2010-AdG_20100317
Summary Breast, prostate, lung and colorectal cancer as solid tumours derived from epithelial tissues are responsible for 90% of all new cancers in Europe. Present tumour staging is mainly based on local tumour extension, metastatic lymph node involvement and evidence of overt distant metastasis obtained by imaging technologies. However, these staging procedures are not sensitive enough to detect early tumour cell dissemination as a key event in tumour progression. Our team has therefore focused on the development of ultrasensitive assays that allow the specific detection and molecular characterization of single tumour cells in bone marrow (DTC) and blood (CTC) of cancer patients. These methods allow the direct assessment of disseminating tumour cells including the detection of therapeutic targets and mechanisms of resistance in patients undergoing therapy. Based on our established network of clinical collaborations, the DISSECT project will detect and characterize DTC/CTC in patients with the four most frequent tumour entities in the EU by high resolution methods. We will investigate representative clinical studies for current interventions that may have an impact on tumour cell dissemination, including diagnostic biopsies, surgical resection of the primary tumour, radiotherapy, chemotherapy and in particular targeted therapies. The technologies for DTC/CTC analyses previously developed by our team will be complemented by cutting-edge technologies and adapted to the analysis to decisive molecular processes underlying the particular intervention. The results obtained in the DISSECT project will provide unique insights into the biology of tumour cell spread in humans and these insights might lead to improved concepts in the clinical management of cancer patients.
Summary
Breast, prostate, lung and colorectal cancer as solid tumours derived from epithelial tissues are responsible for 90% of all new cancers in Europe. Present tumour staging is mainly based on local tumour extension, metastatic lymph node involvement and evidence of overt distant metastasis obtained by imaging technologies. However, these staging procedures are not sensitive enough to detect early tumour cell dissemination as a key event in tumour progression. Our team has therefore focused on the development of ultrasensitive assays that allow the specific detection and molecular characterization of single tumour cells in bone marrow (DTC) and blood (CTC) of cancer patients. These methods allow the direct assessment of disseminating tumour cells including the detection of therapeutic targets and mechanisms of resistance in patients undergoing therapy. Based on our established network of clinical collaborations, the DISSECT project will detect and characterize DTC/CTC in patients with the four most frequent tumour entities in the EU by high resolution methods. We will investigate representative clinical studies for current interventions that may have an impact on tumour cell dissemination, including diagnostic biopsies, surgical resection of the primary tumour, radiotherapy, chemotherapy and in particular targeted therapies. The technologies for DTC/CTC analyses previously developed by our team will be complemented by cutting-edge technologies and adapted to the analysis to decisive molecular processes underlying the particular intervention. The results obtained in the DISSECT project will provide unique insights into the biology of tumour cell spread in humans and these insights might lead to improved concepts in the clinical management of cancer patients.
Max ERC Funding
2 499 000 €
Duration
Start date: 2011-08-01, End date: 2016-07-31
Project acronym EPINORC
Project Epigenetic Disruption of Non-Coding RNAs in Human Cancer
Researcher (PI) Manel Esteller Badosa
Host Institution (HI) FUNDACIO INSTITUT D'INVESTIGACIO BIOMEDICA DE BELLVITGE
Call Details Advanced Grant (AdG), LS4, ERC-2010-AdG_20100317
Summary In recent years, my laboratory, as well as others, have established the observation that epigenetic disruption, particularly in the DNA methylation and histone modification patterns, contributes to the initiation and progression of human tumors (Esteller, Nat Rev Genet 2007; Esteller, N Engl J Med 2008; Esteller, Nat Rev Biotech, In Press, 2010). Even more recently, it has been recognized that microRNAs, small non-coding RNAs that are thought to regulate gene expression by sequence-specific base pairing in mRNA targets, also play a key role in the biology of the cell, and that they can also have an impact in the development of many diseases, including cancer (le Sage and Agami, 2006; Blenkiron and Miska, 2007). However, there is little understanding about epigenetic modifications that might regulate the activity of microRNAs and other non-coding RNAs (ncRNAs), such as long non-coding RNAs (lncRNAs), Piwi-interacting RNAs (piRNAs), small-interfering RNAs (siRNAs), transcribed ultraconserved regions (T-UCRs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), long interspersed ncRNAs (lincRNAs), promoter-associated RNAs (PASRs and PALRs) and terminator-associated sRNAs (TASRs) (Calin et al., 2007; Mercer, et al., 2009; Ghildiyal & Zamore, 2009; Jacquier, 2009). Our ignorance in this respect is even more significant if we consider these questions in the domain of cancer. Making best use of our expertise in several of these fields, my group will tackle the study of the epigenetic modifications that regulate ncRNA expression and how the DNA methylation and histone modifications profiles of these loci might become distorted in human cancer. These findings could have profound consequences not only in the understading of tumor biology, but in the design of better molecular staging, diagnosis and treatments of human malignancies.
Summary
In recent years, my laboratory, as well as others, have established the observation that epigenetic disruption, particularly in the DNA methylation and histone modification patterns, contributes to the initiation and progression of human tumors (Esteller, Nat Rev Genet 2007; Esteller, N Engl J Med 2008; Esteller, Nat Rev Biotech, In Press, 2010). Even more recently, it has been recognized that microRNAs, small non-coding RNAs that are thought to regulate gene expression by sequence-specific base pairing in mRNA targets, also play a key role in the biology of the cell, and that they can also have an impact in the development of many diseases, including cancer (le Sage and Agami, 2006; Blenkiron and Miska, 2007). However, there is little understanding about epigenetic modifications that might regulate the activity of microRNAs and other non-coding RNAs (ncRNAs), such as long non-coding RNAs (lncRNAs), Piwi-interacting RNAs (piRNAs), small-interfering RNAs (siRNAs), transcribed ultraconserved regions (T-UCRs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), long interspersed ncRNAs (lincRNAs), promoter-associated RNAs (PASRs and PALRs) and terminator-associated sRNAs (TASRs) (Calin et al., 2007; Mercer, et al., 2009; Ghildiyal & Zamore, 2009; Jacquier, 2009). Our ignorance in this respect is even more significant if we consider these questions in the domain of cancer. Making best use of our expertise in several of these fields, my group will tackle the study of the epigenetic modifications that regulate ncRNA expression and how the DNA methylation and histone modifications profiles of these loci might become distorted in human cancer. These findings could have profound consequences not only in the understading of tumor biology, but in the design of better molecular staging, diagnosis and treatments of human malignancies.
Max ERC Funding
2 497 240 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym ERA
Project Experimental Research into Ageing
Researcher (PI) Linda Partridge
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Advanced Grant (AdG), LS4, ERC-2010-AdG_20100317
Summary The diseases of older age are a major challenge to human societies. Despite the complexity of ageing, both reduced food intake (dietary restriction) and simple genetic alterations can greatly increase lifespan and provide broad-spectrum protection against diseases of ageing in laboratory animals. Furthermore, there is strong evolutionary conservation of mechanisms. For instance the nutrient-sensing insulin/IGF and TOR signalling network modulates lifespan in yeast, invertebrates and rodents. There is thus a major scientific opportunity to use model organisms to discover how to ameliorate ageing and hence to protect against ageing-related disease in humans. Our recent findings on dietary amino acid balance in the fruit fly Drosophila imply that consumption of nutrients irrelevant to metabolism is life-shortening. Using a novel genomic approach, we shall determine if the same is true in mice and measure the role of dietary imbalance in extension of lifespan by dietary restriction. Late life dietary restriction in invertebrates can increase future survival as much as permanent restriction, implying that chemical mimetics administered late in life could also be fully effective. We shall determine if dietary restriction in mice has similarly acute effects, and use dietary switches to identify candidate mechanisms of increased health and lifespan. Recent evidence has pointed to particular components of nutrient-sensing pathways as promising drug targets for prevention of age-related disease, and we shall investigate two candidates. The work will break new ground in understanding how ageing is modulated by diet and signaling pathways and point to interventions that could protect against the effects of ageing to reduce the burden of ageing-related disease in humans.
Summary
The diseases of older age are a major challenge to human societies. Despite the complexity of ageing, both reduced food intake (dietary restriction) and simple genetic alterations can greatly increase lifespan and provide broad-spectrum protection against diseases of ageing in laboratory animals. Furthermore, there is strong evolutionary conservation of mechanisms. For instance the nutrient-sensing insulin/IGF and TOR signalling network modulates lifespan in yeast, invertebrates and rodents. There is thus a major scientific opportunity to use model organisms to discover how to ameliorate ageing and hence to protect against ageing-related disease in humans. Our recent findings on dietary amino acid balance in the fruit fly Drosophila imply that consumption of nutrients irrelevant to metabolism is life-shortening. Using a novel genomic approach, we shall determine if the same is true in mice and measure the role of dietary imbalance in extension of lifespan by dietary restriction. Late life dietary restriction in invertebrates can increase future survival as much as permanent restriction, implying that chemical mimetics administered late in life could also be fully effective. We shall determine if dietary restriction in mice has similarly acute effects, and use dietary switches to identify candidate mechanisms of increased health and lifespan. Recent evidence has pointed to particular components of nutrient-sensing pathways as promising drug targets for prevention of age-related disease, and we shall investigate two candidates. The work will break new ground in understanding how ageing is modulated by diet and signaling pathways and point to interventions that could protect against the effects of ageing to reduce the burden of ageing-related disease in humans.
Max ERC Funding
2 489 200 €
Duration
Start date: 2011-06-01, End date: 2016-05-31
Project acronym GENE TARGET T2D
Project General and targeted approaches to unravel the molecular causes of type 2 diabetes
Researcher (PI) Leif Christer Groop
Host Institution (HI) LUNDS UNIVERSITET
Call Details Advanced Grant (AdG), LS4, ERC-2010-AdG_20100317
Summary Type 2 diabetes (T2D) affects worldwide at present about 250 million patients and an estimated 380 million in 2025. This epidemic has been ascribed to a collision between genes and an affluent society. Genetics of T2D has during recent years identified > 30 variants increasing susceptibility to T2D. Yet, these variants explain only 15% of the heritability of T2D. One reason could be that whole genome association studies can only detect common variants whereas identification of rare variants with stronger effects would require sequencing. A large part of this application is devoted to sequencing of affected family members from unique large pedigrees traced back to common ancestors around 1600. The advantage of using families is that identified variants can be tested for segregation with the trait. Genetic variants can influence expression of a gene in an allele specific manner. This will be explored by combining exome sequencing with sequencing of RNA from human islets.
Impaired effects of the incretin hormones GLP-1 and GIP on the pancreatic islets represent central defects in T2D. Variants in the TCF7L2 and GIPR genes contribute to these defects. I will here explore the molecular mechanisms by which TCF7L2, the strongest T2D gene, causes T2D. GIP has unprecedented effects not only on islet function but also on body composition, blood flow and vascular complications in T2D. This application explores these effects and will test whether manipulation of GIP can mimic the normalization of glucose tolerance seen after gastric bypass surgery.
Taken together, these general and targeted approaches are expected not only to provide new insights into the causes of T2D but also contribute with vital information for development of new treatments for T2D.
Summary
Type 2 diabetes (T2D) affects worldwide at present about 250 million patients and an estimated 380 million in 2025. This epidemic has been ascribed to a collision between genes and an affluent society. Genetics of T2D has during recent years identified > 30 variants increasing susceptibility to T2D. Yet, these variants explain only 15% of the heritability of T2D. One reason could be that whole genome association studies can only detect common variants whereas identification of rare variants with stronger effects would require sequencing. A large part of this application is devoted to sequencing of affected family members from unique large pedigrees traced back to common ancestors around 1600. The advantage of using families is that identified variants can be tested for segregation with the trait. Genetic variants can influence expression of a gene in an allele specific manner. This will be explored by combining exome sequencing with sequencing of RNA from human islets.
Impaired effects of the incretin hormones GLP-1 and GIP on the pancreatic islets represent central defects in T2D. Variants in the TCF7L2 and GIPR genes contribute to these defects. I will here explore the molecular mechanisms by which TCF7L2, the strongest T2D gene, causes T2D. GIP has unprecedented effects not only on islet function but also on body composition, blood flow and vascular complications in T2D. This application explores these effects and will test whether manipulation of GIP can mimic the normalization of glucose tolerance seen after gastric bypass surgery.
Taken together, these general and targeted approaches are expected not only to provide new insights into the causes of T2D but also contribute with vital information for development of new treatments for T2D.
Max ERC Funding
2 499 480 €
Duration
Start date: 2011-05-01, End date: 2016-04-30
Project acronym HIFHEPC
Project HIF and hepcidin : missing links between infection, iron metabolism and cancer ?
Researcher (PI) Carole Sophie Isabelle Peyssonnaux
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS4, ERC-2010-StG_20091118
Summary HIF transcription factors, central mediators of cellular adaptation to critically low oxygen levels (=hypoxia), have been largely studied for their crucial role during cancer development. Our recent findings have unveiled two new major roles of HIF. First, in innate immunity and infection, we demonstrated the key contributions of HIFs in regulating important immune effectors molecules. Second, we highlighted the role of HIFs in iron metabolism as critical regulators of iron absorption in the intestine and in systemic iron homeostasis by regulating the liver synthesis of the iron regulatory hormone, hepcidin.
These results open new research areas and our research program, based on unique mouse models of conditional HIFs and hepcidin knockout, will be developed around three main axes.
1) define the physiological roles of HIF and hepcidin in different key organs involved in maintaining body iron homeostasis. A detailed understanding of the regulation of iron-related proteins is a prerequisite in the development of therapeutics for iron diseases, which pose a major problem worldwide.
2) study the role of hepcidin during bacterial infection and tumorigenesis, two pathological conditions where iron is critically required for the proliferation of the pathogens and for cancer cells to feed their high metabolic activity.
3) determine the contribution of HIFs in the initiation of tumor development in response to infection. Indeed, our findings that HIF is stabilized by bacteria, even under normal levels of oxygen, and is an essential component of the inflammation response, let us to speculate that HIFs may be a missing link between infection and cancer by triggering a high chronic inflammatory response. For that, we will use the model of the gastric cancer, whose the initiating event is an infection by Helicobacter Pylori.
Summary
HIF transcription factors, central mediators of cellular adaptation to critically low oxygen levels (=hypoxia), have been largely studied for their crucial role during cancer development. Our recent findings have unveiled two new major roles of HIF. First, in innate immunity and infection, we demonstrated the key contributions of HIFs in regulating important immune effectors molecules. Second, we highlighted the role of HIFs in iron metabolism as critical regulators of iron absorption in the intestine and in systemic iron homeostasis by regulating the liver synthesis of the iron regulatory hormone, hepcidin.
These results open new research areas and our research program, based on unique mouse models of conditional HIFs and hepcidin knockout, will be developed around three main axes.
1) define the physiological roles of HIF and hepcidin in different key organs involved in maintaining body iron homeostasis. A detailed understanding of the regulation of iron-related proteins is a prerequisite in the development of therapeutics for iron diseases, which pose a major problem worldwide.
2) study the role of hepcidin during bacterial infection and tumorigenesis, two pathological conditions where iron is critically required for the proliferation of the pathogens and for cancer cells to feed their high metabolic activity.
3) determine the contribution of HIFs in the initiation of tumor development in response to infection. Indeed, our findings that HIF is stabilized by bacteria, even under normal levels of oxygen, and is an essential component of the inflammation response, let us to speculate that HIFs may be a missing link between infection and cancer by triggering a high chronic inflammatory response. For that, we will use the model of the gastric cancer, whose the initiating event is an infection by Helicobacter Pylori.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-06-01, End date: 2016-05-31
Project acronym HUFATREG
Project Adipose tissue mass regulation in lean and obese individuals
Researcher (PI) Kirsty Lee Spalding
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS4, ERC-2010-StG_20091118
Summary Owing to the increase in obesity, life expectancy may start to decrease in developed countries for the first time in recent history. In humans the generation of fat cells (adipocytes) is a major factor behind the growth of adipose tissue during childhood. The factors determining the fat mass in adults, however, are not fully understood. Increased fat storage in fully differentiated adipocytes, resulting in enlarged fat cells, is well documented and thought to be the most important mechanism whereby fat depots increase in adults. Very little is known about the maintenance of fat cells (adipocytes) in humans, how different fat depots are maintained and how (or if) this is altered in obesity. Recently I developed a method that is based on the incorporation of 14C from nuclear bomb tests into genomic DNA, which allows for the analysis of cell and tissue turnover in humans. Using this novel methodology we now have a strategy for studying cell turnover in humans. One tissue of great interest and significant clinical relevance is adipose tissue. Excess adipose tissue, resulting in obesity, is currently one of the most serious threats to human health on a global level. The current proposal aims to determine the dynamics of human adipose tissue maintenance and investigate any differences in regulation of the fat mass in lean and obese individuals. Understanding the dynamics of adipocyte turnover may shed new light on potential treatments for obesity.
Summary
Owing to the increase in obesity, life expectancy may start to decrease in developed countries for the first time in recent history. In humans the generation of fat cells (adipocytes) is a major factor behind the growth of adipose tissue during childhood. The factors determining the fat mass in adults, however, are not fully understood. Increased fat storage in fully differentiated adipocytes, resulting in enlarged fat cells, is well documented and thought to be the most important mechanism whereby fat depots increase in adults. Very little is known about the maintenance of fat cells (adipocytes) in humans, how different fat depots are maintained and how (or if) this is altered in obesity. Recently I developed a method that is based on the incorporation of 14C from nuclear bomb tests into genomic DNA, which allows for the analysis of cell and tissue turnover in humans. Using this novel methodology we now have a strategy for studying cell turnover in humans. One tissue of great interest and significant clinical relevance is adipose tissue. Excess adipose tissue, resulting in obesity, is currently one of the most serious threats to human health on a global level. The current proposal aims to determine the dynamics of human adipose tissue maintenance and investigate any differences in regulation of the fat mass in lean and obese individuals. Understanding the dynamics of adipocyte turnover may shed new light on potential treatments for obesity.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-04-01, End date: 2017-03-31
