Project acronym CFS modelling
Project Chromosomal Common Fragile Sites: Unravelling their biological functions and the basis of their instability
Researcher (PI) Andres Joaquin Lopez-Contreras
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Starting Grant (StG), LS4, ERC-2015-STG
Summary Cancer and other diseases are driven by genomic alterations initiated by DNA breaks. Within our genomes, some regions are particularly prone to breakage, and these are known as common fragile sites (CFSs). CFSs are present in every person and are frequently sites of oncogenic chromosomal rearrangements. Intriguingly, despite their fragility, many CFSs are well conserved through evolution, suggesting that these regions have important physiological functions that remain elusive. My previous background in genome editing, proteomics and replication-born DNA damage has given me the tools to propose an ambitious and comprehensive plan that tackles fundamental questions on the biology of CFSs. First, we will perform a systematic analysis of the function of CFSs. Most of the CFSs contain very large genes, which has made technically difficult to dissect whether the CFS role is due to the locus itself or to the encoded gene product. However, the emergence of the CRISPR/Cas9 technology now enables the study of CFSs on a more systematic basis. We will pioneer the engineering of mammalian models harbouring large deletions at CFS loci to investigate their physiological functions at the cellular and organism levels. For those CFSs that contain genes, the cDNAs will be re-introduced at a distal locus. Using this strategy, we will be able to achieve the first comprehensive characterization of CFS roles. Second, we will develop novel targeted approaches to interrogate the chromatin-bound proteome of CFSs and its dynamics during DNA replication. Finally, and given that CFS fragility is influenced both by cell cycle checkpoints and dNTP availability, we will use mouse models to study the impact of ATR/CHK1 pathway and dNTP levels on CFS instability and cancer. Taken together, I propose an ambitious, yet feasible, project to functionally annotate and characterise these poorly understood regions of the human genome, with important potential implications for improving human health.
Summary
Cancer and other diseases are driven by genomic alterations initiated by DNA breaks. Within our genomes, some regions are particularly prone to breakage, and these are known as common fragile sites (CFSs). CFSs are present in every person and are frequently sites of oncogenic chromosomal rearrangements. Intriguingly, despite their fragility, many CFSs are well conserved through evolution, suggesting that these regions have important physiological functions that remain elusive. My previous background in genome editing, proteomics and replication-born DNA damage has given me the tools to propose an ambitious and comprehensive plan that tackles fundamental questions on the biology of CFSs. First, we will perform a systematic analysis of the function of CFSs. Most of the CFSs contain very large genes, which has made technically difficult to dissect whether the CFS role is due to the locus itself or to the encoded gene product. However, the emergence of the CRISPR/Cas9 technology now enables the study of CFSs on a more systematic basis. We will pioneer the engineering of mammalian models harbouring large deletions at CFS loci to investigate their physiological functions at the cellular and organism levels. For those CFSs that contain genes, the cDNAs will be re-introduced at a distal locus. Using this strategy, we will be able to achieve the first comprehensive characterization of CFS roles. Second, we will develop novel targeted approaches to interrogate the chromatin-bound proteome of CFSs and its dynamics during DNA replication. Finally, and given that CFS fragility is influenced both by cell cycle checkpoints and dNTP availability, we will use mouse models to study the impact of ATR/CHK1 pathway and dNTP levels on CFS instability and cancer. Taken together, I propose an ambitious, yet feasible, project to functionally annotate and characterise these poorly understood regions of the human genome, with important potential implications for improving human health.
Max ERC Funding
1 499 711 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
Project acronym CureCKDHeart
Project Targeting perivascular myofibroblast progenitors to treat cardiac fibrosis and heart failure in chronic kidney disease
Researcher (PI) Rafael Johannes Thomas Kramann
Host Institution (HI) UNIVERSITAETSKLINIKUM AACHEN
Call Details Starting Grant (StG), LS4, ERC-2015-STG
Summary Chronic kidney disease (CKD) is a growing public health problem with a massively increased cardiovascular mortality. Patients with advanced CKD mostly die from sudden cardiac death and recurrent heart failure due to premature cardiac aging with hypertrophy, fibrosis, and capillary rarefaction. I have recently identified the long sought key cardiac myofibroblast progenitor population, an emerging breakthrough that carries the potential to develop novel targeted therapeutics. Genetic ablation of these Gli1+ perivascular progenitors ameliorates fibrosis, cardiac hypertrophy and rescues left-ventricular function. I propose that Gli1+ cells are critically involved in all major pathophysiologic changes in cardiac aging and uremic cardiomyopathy including fibrosis, hypertrophy and capillary rarefaction. I will perform state of the art genetic fate tracing, ablation and in vivo CRISPR/Cas9 genome editing experiments to untangle their complex mechanism of activation and communication with endothelial cells and cardiomyocytes promoting fibrosis, capillary rarefaction, cardiac hypertrophy and heart failure. To identify novel druggable targets I will utilize new mouse models that allow comparative transcript and proteasome profiling assays of these critical myofibroblast precusors in homeostasis, aging and premature aging in CKD. Novel assays with immortalized cardiac Gli1+ cells will allow high throughput screens to identify uremia associated factors of cell activation and inhibitory compounds to facilitate the development of novel therapeutics.
This ambitious interdisciplinary project requires the expertise of chemists, physiologists, biomedical researchers and physician scientists to develop novel targeted therapies in cardiac remodeling during aging and CKD. The passion that drives this project results from a simple emerging hypothesis: It is possible to treat heart failure and sudden cardiac death in aging and CKD by targeting perivascular myofibroblast progenitors.
Summary
Chronic kidney disease (CKD) is a growing public health problem with a massively increased cardiovascular mortality. Patients with advanced CKD mostly die from sudden cardiac death and recurrent heart failure due to premature cardiac aging with hypertrophy, fibrosis, and capillary rarefaction. I have recently identified the long sought key cardiac myofibroblast progenitor population, an emerging breakthrough that carries the potential to develop novel targeted therapeutics. Genetic ablation of these Gli1+ perivascular progenitors ameliorates fibrosis, cardiac hypertrophy and rescues left-ventricular function. I propose that Gli1+ cells are critically involved in all major pathophysiologic changes in cardiac aging and uremic cardiomyopathy including fibrosis, hypertrophy and capillary rarefaction. I will perform state of the art genetic fate tracing, ablation and in vivo CRISPR/Cas9 genome editing experiments to untangle their complex mechanism of activation and communication with endothelial cells and cardiomyocytes promoting fibrosis, capillary rarefaction, cardiac hypertrophy and heart failure. To identify novel druggable targets I will utilize new mouse models that allow comparative transcript and proteasome profiling assays of these critical myofibroblast precusors in homeostasis, aging and premature aging in CKD. Novel assays with immortalized cardiac Gli1+ cells will allow high throughput screens to identify uremia associated factors of cell activation and inhibitory compounds to facilitate the development of novel therapeutics.
This ambitious interdisciplinary project requires the expertise of chemists, physiologists, biomedical researchers and physician scientists to develop novel targeted therapies in cardiac remodeling during aging and CKD. The passion that drives this project results from a simple emerging hypothesis: It is possible to treat heart failure and sudden cardiac death in aging and CKD by targeting perivascular myofibroblast progenitors.
Max ERC Funding
1 497 888 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
Project acronym EVI1inCancer
Project Overcoming the epigenetic and therapeutic barrier of EVI1-overexpressing cancers
Researcher (PI) Stefan Gröschel
Host Institution (HI) DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Call Details Starting Grant (StG), LS4, ERC-2015-STG
Summary Deregulation of the EVI1 oncogene is a key transforming event in the development of many malignancies, most prominently very high-risk acute myeloid leukemia (AML), ovarian, colon, breast, non-small cell lung cancer, and soft-tissue sarcoma. For decades, both EVI1 function and the mechanism underlying its deregulation have been poorly understood. The consequent lack of a targeted therapy against EVI1 establishes a pressing medical need. In a recent study investigating a distinct category of EVI1-driven AML with inv(3) or t(3;3), we characterized the regulatory domain of EVI1 and identified a master regulatory element of the stemness factor GATA2 to be rearranged to EVI1, thereby deregulating both genes. Applying functional genomics and genome-editing, we found that the rearranged enhancer element adopted novel features, such as superloading of the epigenetic reader and chromatin regulator BRD4, allowing its inhibition with BET/bromodomain inhibitors with relative EVI1 specificity. Interference with EVI1-regulatory mechanisms thus has potential therapeutic value in EVI1-transformed tumors. To pave the way for epigenetic targeting of other EVI1-expressing malignancies, we aim to identify genomic enhancer sequences and protein components of the EVI1 regulatory domain by systematic epigenetic and proteomic profiling. Specifically, we seek to achieve the following experimental goals: (1) Identification of the mechanism underlying EVI1 deregulation in non-3q-rearranged AML and solid tumors; (2) Addressing the role of breakpoint-associated transpos-able retroelements; (3) Characterization of the transcription factor complex regulating EVI1; (4) Identification of epigenetic resistance mechanisms in EVI1+ AML by using an in vivo model and a genome-editing approach. The proposed experiments will provide insight into the epigenetic landscape of EVI1+ malignancies and help reveal new targets and genetic interactions amenable to future therapies in these high-risk malignancies.
Summary
Deregulation of the EVI1 oncogene is a key transforming event in the development of many malignancies, most prominently very high-risk acute myeloid leukemia (AML), ovarian, colon, breast, non-small cell lung cancer, and soft-tissue sarcoma. For decades, both EVI1 function and the mechanism underlying its deregulation have been poorly understood. The consequent lack of a targeted therapy against EVI1 establishes a pressing medical need. In a recent study investigating a distinct category of EVI1-driven AML with inv(3) or t(3;3), we characterized the regulatory domain of EVI1 and identified a master regulatory element of the stemness factor GATA2 to be rearranged to EVI1, thereby deregulating both genes. Applying functional genomics and genome-editing, we found that the rearranged enhancer element adopted novel features, such as superloading of the epigenetic reader and chromatin regulator BRD4, allowing its inhibition with BET/bromodomain inhibitors with relative EVI1 specificity. Interference with EVI1-regulatory mechanisms thus has potential therapeutic value in EVI1-transformed tumors. To pave the way for epigenetic targeting of other EVI1-expressing malignancies, we aim to identify genomic enhancer sequences and protein components of the EVI1 regulatory domain by systematic epigenetic and proteomic profiling. Specifically, we seek to achieve the following experimental goals: (1) Identification of the mechanism underlying EVI1 deregulation in non-3q-rearranged AML and solid tumors; (2) Addressing the role of breakpoint-associated transpos-able retroelements; (3) Characterization of the transcription factor complex regulating EVI1; (4) Identification of epigenetic resistance mechanisms in EVI1+ AML by using an in vivo model and a genome-editing approach. The proposed experiments will provide insight into the epigenetic landscape of EVI1+ malignancies and help reveal new targets and genetic interactions amenable to future therapies in these high-risk malignancies.
Max ERC Funding
1 499 094 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym IMCIS
Project Individualised medicine in chronic inflammatory skin diseases
Researcher (PI) Kilian Georg Eyerich
Host Institution (HI) KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary More than 100 million EU citizens suffer from chronic inflammatory skin diseases such as psoriasis and atopic eczema (AE). The diseases imply a devastating life quality similar to that of cancer, and cause direct socio-economic costs in the magnitude of 100 billion Euro each year in the EU. Despite all efforts, psoriasis and AE remain undertreated and the concept of individualised (also called precision) medicine could not be established in the field. Consequently, intensified research is demanded by organisations such as the WHO. Unmet medical needs are 1) a diagnostic gap, 2) lack of prediction possibilities to define the optimal therapy for an individual patient, and 3) a substantial number of non-responders to therapies. Reasons for these shortcomings are the heterogeneity of both psoriasis and AE and insufficient collaboration of clinical specialists, basic researchers, and bio-informaticians. This proposal aims at improving health care of inflammatory skin diseases by implying the concept of individualised medicine. The crucial step towards this goal is the ground-breaking idea to link deep clinical phenotyping to molecular signatures in lesional skin. Deep phenotyping means each patient is characterised by 86 clinical, histological, and laboratory attributes rather than the imprecise state-of-the art approach of rough diagnosing. Each attribute gets assigned to molecular events in lesional skin. Gene regions as well as key pathogenic molecules are identified in a novel gene network of inflamed skin, referred to as BRAIN (biological relevance assigned intelligent network). Candidate targets get validated using state-of-the-art cell culture systems and full skin models. This innovative and ambitious approach will substantially improve our knowledge of the pathogenesis and primary triggers of both psoriasis and AE, safe European health care systems direct costs in the magnitude of 10 billion Euro, and have a model character for complex diseases in general.
Summary
More than 100 million EU citizens suffer from chronic inflammatory skin diseases such as psoriasis and atopic eczema (AE). The diseases imply a devastating life quality similar to that of cancer, and cause direct socio-economic costs in the magnitude of 100 billion Euro each year in the EU. Despite all efforts, psoriasis and AE remain undertreated and the concept of individualised (also called precision) medicine could not be established in the field. Consequently, intensified research is demanded by organisations such as the WHO. Unmet medical needs are 1) a diagnostic gap, 2) lack of prediction possibilities to define the optimal therapy for an individual patient, and 3) a substantial number of non-responders to therapies. Reasons for these shortcomings are the heterogeneity of both psoriasis and AE and insufficient collaboration of clinical specialists, basic researchers, and bio-informaticians. This proposal aims at improving health care of inflammatory skin diseases by implying the concept of individualised medicine. The crucial step towards this goal is the ground-breaking idea to link deep clinical phenotyping to molecular signatures in lesional skin. Deep phenotyping means each patient is characterised by 86 clinical, histological, and laboratory attributes rather than the imprecise state-of-the art approach of rough diagnosing. Each attribute gets assigned to molecular events in lesional skin. Gene regions as well as key pathogenic molecules are identified in a novel gene network of inflamed skin, referred to as BRAIN (biological relevance assigned intelligent network). Candidate targets get validated using state-of-the-art cell culture systems and full skin models. This innovative and ambitious approach will substantially improve our knowledge of the pathogenesis and primary triggers of both psoriasis and AE, safe European health care systems direct costs in the magnitude of 10 billion Euro, and have a model character for complex diseases in general.
Max ERC Funding
1 495 906 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym INTEGHER
Project Integration of herpesvirus into telomeres: From the mechanism of genome integration and mobilization to therapeutic intervention
Researcher (PI) Benedikt Kaufer
Host Institution (HI) FREIE UNIVERSITAET BERLIN
Call Details Starting Grant (StG), LS6, ERC-2015-STG
Summary Herpesviruses cause serious diseases in humans and animals. After initial lytic infection, herpesviruses establish a quiescent (latent) infection, which allows their persistence in the host for life. We and others recently identified a novel mechanism that allows maintenance of the genome of certain herpesviruses during latency, by integrating their complete genetic material into host telomeres. One of these viruses is human herpesvirus 6 (HHV-6) which is associated with seizures, encephalitis, and graft rejection in transplant patients. Sporadic reactivation of the integrated virus ensures continued evolution of the virus as it spreads to a new cadre of susceptible individuals. There are critical gaps in our knowledge regarding the fate of herpesvirus genomes during integration and reactivation as well as of viral and cellular factors involved in these processes.
INTEGHER will make use of novel technologies to close these gaps and to devise new therapeutic approaches. Specifically, we will 1) determine the fate of the HHV-6 genome during latency by developing a novel reporter system that allows live-cell imaging of the virus genome in living cells and elucidate epigenetic changes of the HHV-6 genome during integration and reactivation; 2) identify viral and cellular factors that drive virus genome integration and reactivation, using recombinant viruses, drugs and CRISPR/Cas9 genome engineering 3) employ genome-editing tools to eliminate the virus genome integrated in host chromosomes in vitro and in an in vivo model. The proposal utilizes state-of-the-art technologies and pioneers new approaches, particularly with regard to visualization and excision of virus genomes in latently infected cells that are also present in (bone marrow) transplants. Altogether, these studies will define the mechanism of herpesvirus integration and reactivation and will provide new tools for therapeutic excision of virus genomes from living cells.
Summary
Herpesviruses cause serious diseases in humans and animals. After initial lytic infection, herpesviruses establish a quiescent (latent) infection, which allows their persistence in the host for life. We and others recently identified a novel mechanism that allows maintenance of the genome of certain herpesviruses during latency, by integrating their complete genetic material into host telomeres. One of these viruses is human herpesvirus 6 (HHV-6) which is associated with seizures, encephalitis, and graft rejection in transplant patients. Sporadic reactivation of the integrated virus ensures continued evolution of the virus as it spreads to a new cadre of susceptible individuals. There are critical gaps in our knowledge regarding the fate of herpesvirus genomes during integration and reactivation as well as of viral and cellular factors involved in these processes.
INTEGHER will make use of novel technologies to close these gaps and to devise new therapeutic approaches. Specifically, we will 1) determine the fate of the HHV-6 genome during latency by developing a novel reporter system that allows live-cell imaging of the virus genome in living cells and elucidate epigenetic changes of the HHV-6 genome during integration and reactivation; 2) identify viral and cellular factors that drive virus genome integration and reactivation, using recombinant viruses, drugs and CRISPR/Cas9 genome engineering 3) employ genome-editing tools to eliminate the virus genome integrated in host chromosomes in vitro and in an in vivo model. The proposal utilizes state-of-the-art technologies and pioneers new approaches, particularly with regard to visualization and excision of virus genomes in latently infected cells that are also present in (bone marrow) transplants. Altogether, these studies will define the mechanism of herpesvirus integration and reactivation and will provide new tools for therapeutic excision of virus genomes from living cells.
Max ERC Funding
1 810 747 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym nextDART
Project Next-generation Detection of Antigen Responsive T-cells
Researcher (PI) Sine Reker Hadrup
Host Institution (HI) DANMARKS TEKNISKE UNIVERSITET
Call Details Starting Grant (StG), LS6, ERC-2015-STG
Summary Our current ability to map T-cell reactivity to certain molecular patterns poorly matches the huge diversity of T-cell recognition in humans. Our immune system holds approximately 107 different T-cell populations patrolling our body to fight intruding pathogens. Current state-of-the-art T-cell detection enables the detection of 45 different T-cell specificities in a given sample. Therefore comprehensive analysis of T-cell recognition against intruding pathogens, auto-immune attacked tissues or cancer is virtually impossible.
To gain insight into immune recognition and allow careful target selection for disease intervention, also on a personalized basis, we need technologies that allow detection of vast numbers of different T-cell specificities with high sensitivity in small biological samples.
I propose here a new technology based on multimerised peptide-major histocompatibility complex I (MHC I) reagents that allow detection of >1000 different T-cell specificities with high sensitivity in small biological samples. I will use this new technology to gain insight into the T-cell recognition of cancer cells and specifically assess the impact of mutation-derived neo-epitopes on T cell-mediated cancer cell recognition.
A major advantage of this new technology relates to the ability of coupling the antigen specificity to the T-cell receptor sequence. This will enable us to retrieve information about T-cell receptor sequences coupled with their molecular recognition pattern, and develop a predictor of binding between T-cell receptors and specific epitopes. It will ultimately enable us to predict immune recognition based on T-cell receptor sequences, and has the potential to truly transform our understanding of T cell immunology.
Advances in our understanding of T cell immunology are leading to massive advances in the treatment of cancer. The technologies I propose to develop and validate will greatly aid this process and have application for all immune related diseases.
Summary
Our current ability to map T-cell reactivity to certain molecular patterns poorly matches the huge diversity of T-cell recognition in humans. Our immune system holds approximately 107 different T-cell populations patrolling our body to fight intruding pathogens. Current state-of-the-art T-cell detection enables the detection of 45 different T-cell specificities in a given sample. Therefore comprehensive analysis of T-cell recognition against intruding pathogens, auto-immune attacked tissues or cancer is virtually impossible.
To gain insight into immune recognition and allow careful target selection for disease intervention, also on a personalized basis, we need technologies that allow detection of vast numbers of different T-cell specificities with high sensitivity in small biological samples.
I propose here a new technology based on multimerised peptide-major histocompatibility complex I (MHC I) reagents that allow detection of >1000 different T-cell specificities with high sensitivity in small biological samples. I will use this new technology to gain insight into the T-cell recognition of cancer cells and specifically assess the impact of mutation-derived neo-epitopes on T cell-mediated cancer cell recognition.
A major advantage of this new technology relates to the ability of coupling the antigen specificity to the T-cell receptor sequence. This will enable us to retrieve information about T-cell receptor sequences coupled with their molecular recognition pattern, and develop a predictor of binding between T-cell receptors and specific epitopes. It will ultimately enable us to predict immune recognition based on T-cell receptor sequences, and has the potential to truly transform our understanding of T cell immunology.
Advances in our understanding of T cell immunology are leading to massive advances in the treatment of cancer. The technologies I propose to develop and validate will greatly aid this process and have application for all immune related diseases.
Max ERC Funding
1 499 070 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym PrenatStressAging
Project Prenatal Stress and Programming of Newborn and Infant Telomere Biology and Cellular Aging
Researcher (PI) Sonja Entringer
Host Institution (HI) CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary The long-term consequences of exposure to excess stress on the initiation and progression of many age-related diseases are well established. The period of intrauterine life represents among the most sensitive developmental windows, at which time the effects of stress may be transmitted inter-generationally from a mother to her as-yet-unborn child. The elucidation of mechanisms underlying such effects is an area of intense interest and investigation. Aging, by definition, occurs with advancing age, and age-related disorders result from exposures over the life span of factors that produce and accumulate damage. The novel concept advanced in this proposal is that the establishment of the integrity of key cellular aging-related processes that determine variation across individuals in the onset and progression of age-related disorders may originate very early in life (in utero) and may be plastic and influenced by developmental conditions. We propose that telomere biology and the epigenetic DNA methylation-based aging profile (DNAmAGE) represent candidate outcomes of particular interest in this context. A prospective, longitudinal cohort study of 350 mother-child dyads will be conducted from early pregnancy through birth till one year of age. Specific hypotheses about the effects of maternal stress and maternal-placental-fetal stress biology on newborn and infant telomere length, telomerase expression capacity, and DNAmAGE will be addressed. Serial measures of maternal psychological, behavioral and physiological characteristics will be collected across gestation using an innovative ecological momentary assessment (EMA) based real-time, ambulatory sampling protocol. The proposed study will help identify new strategies for risk identification and primary and secondary interventions to augment current efforts to prevent, delay and ameliorate age-related disorders.
Summary
The long-term consequences of exposure to excess stress on the initiation and progression of many age-related diseases are well established. The period of intrauterine life represents among the most sensitive developmental windows, at which time the effects of stress may be transmitted inter-generationally from a mother to her as-yet-unborn child. The elucidation of mechanisms underlying such effects is an area of intense interest and investigation. Aging, by definition, occurs with advancing age, and age-related disorders result from exposures over the life span of factors that produce and accumulate damage. The novel concept advanced in this proposal is that the establishment of the integrity of key cellular aging-related processes that determine variation across individuals in the onset and progression of age-related disorders may originate very early in life (in utero) and may be plastic and influenced by developmental conditions. We propose that telomere biology and the epigenetic DNA methylation-based aging profile (DNAmAGE) represent candidate outcomes of particular interest in this context. A prospective, longitudinal cohort study of 350 mother-child dyads will be conducted from early pregnancy through birth till one year of age. Specific hypotheses about the effects of maternal stress and maternal-placental-fetal stress biology on newborn and infant telomere length, telomerase expression capacity, and DNAmAGE will be addressed. Serial measures of maternal psychological, behavioral and physiological characteristics will be collected across gestation using an innovative ecological momentary assessment (EMA) based real-time, ambulatory sampling protocol. The proposed study will help identify new strategies for risk identification and primary and secondary interventions to augment current efforts to prevent, delay and ameliorate age-related disorders.
Max ERC Funding
1 483 720 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym ProFatMRI
Project Magnetic resonance imaging platform for probing fat microstructure
Researcher (PI) Dimitrios Karampinos
Host Institution (HI) KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary Metabolic syndrome and osteoporosis are the two metabolic diseases with the highest and most rapidly growing prevalence, transforming them into a major global health and socioeconomic concern. Metabolic syndrome can be diagnosed with established biomarkers, but the selection of optimal prevention strategies for each individual patient is still problematic. Osteoporosis can be treated, but its current early diagnosis remains insufficient. The two diseases have been linked through the role of fat. Fat is central to their incidence and progression, and the probing of fat cellular properties can provide groundbreaking solutions for overcoming the existing challenges in the diseases early diagnosis and prevention.
In metabolic syndrome, there is evidence supporting a role of brown fat in preventing the disease. Brown fat has different microstructure than white fat. However, there is no established non-invasive biomarker to measure brown fat. In osteoporosis, there is evidence supporting a role of marrow fat, in combination with bone mineral density, for monitoring fracture risk. However, there is no non-invasive biomarker to measure marrow fat cellular changes in osteoporosis.
Magnetic resonance imaging (MRI) is the ideal modality for non-invasively measuring fat throughout the body. In order to differentiate brown from white fat and characterize the relationship between bone mineral and marrow fat cells, the employed MR methodology needs a technical breakthrough, shifting from the state-of-the-art water-centered paradigm to a fat-centered microstructural MRI paradigm. ProFatMRI describes an innovative research program that aims to develop and ex vivo validate diffusion and susceptibility MRI biomarkers of fat microstructure, and in vivo apply them at clinical MRI systems.
The resulting technologies will provide novel ways for selecting optimal individualized prevention strategies in metabolic syndrome and for achieving reliable risk fracture prediction in osteoporosis.
Summary
Metabolic syndrome and osteoporosis are the two metabolic diseases with the highest and most rapidly growing prevalence, transforming them into a major global health and socioeconomic concern. Metabolic syndrome can be diagnosed with established biomarkers, but the selection of optimal prevention strategies for each individual patient is still problematic. Osteoporosis can be treated, but its current early diagnosis remains insufficient. The two diseases have been linked through the role of fat. Fat is central to their incidence and progression, and the probing of fat cellular properties can provide groundbreaking solutions for overcoming the existing challenges in the diseases early diagnosis and prevention.
In metabolic syndrome, there is evidence supporting a role of brown fat in preventing the disease. Brown fat has different microstructure than white fat. However, there is no established non-invasive biomarker to measure brown fat. In osteoporosis, there is evidence supporting a role of marrow fat, in combination with bone mineral density, for monitoring fracture risk. However, there is no non-invasive biomarker to measure marrow fat cellular changes in osteoporosis.
Magnetic resonance imaging (MRI) is the ideal modality for non-invasively measuring fat throughout the body. In order to differentiate brown from white fat and characterize the relationship between bone mineral and marrow fat cells, the employed MR methodology needs a technical breakthrough, shifting from the state-of-the-art water-centered paradigm to a fat-centered microstructural MRI paradigm. ProFatMRI describes an innovative research program that aims to develop and ex vivo validate diffusion and susceptibility MRI biomarkers of fat microstructure, and in vivo apply them at clinical MRI systems.
The resulting technologies will provide novel ways for selecting optimal individualized prevention strategies in metabolic syndrome and for achieving reliable risk fracture prediction in osteoporosis.
Max ERC Funding
1 499 566 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym SiCMetabol
Project Signaling Cascades in Metabolic Diseases
Researcher (PI) Grzegorz Piotr Sumara
Host Institution (HI) JULIUS-MAXIMILIANS-UNIVERSITAT WURZBURG
Call Details Starting Grant (StG), LS4, ERC-2015-STG
Summary Over 380 million people suffer from diabetes worldwide, with majority of cases being attributed to type 2 diabetes (T2D). Obesity is a major risk factor predisposing to the development of this disease. T2D is characterized by peripheral insulin resistance in combination with relative insulin deficiency that results in hyperglycemia and hyperlipidemia. Liver and adipose tissue are central for regulation of glucose and lipids levels. However, during T2D the hepatic glucose uptake is reduced while rates of gluconeogenesis and lipogenesis are increased. In the adipose tissue, T2D leads to decreased glucose uptake, perturbations in secretion of adipokines and increased lipolysis. Importantly, dysfunction of the liver and the adipose tissue during T2D is caused by defective phosphorylation signaling cascades and normalization of these pathways was shown to attenuate the course of T2D. However, the specific roles of different classes of signaling molecules in these organs remain poorly characterized. We hypothesize that the cross-talk of different classes of signaling molecules determines regulation of metabolism.
Thus, we aim to identify the signaling networks regulating metabolism. The results generated in my own laboratory suggest that the Pkd family kinases are the crucial regulators of metabolic homeostasis. Specifically, Pkd1 and Pkd2 promote obesity and diabetes while Pkd3 controls liver function. Thus, we plan to characterize the molecular mechanisms controlling Pkds signaling. In parallel, we will utilize screening approaches to identify novel, non-canonical signaling modules (phosphatases and components of the ubiquitin system) regulating abundance, localization and phosphorylation of targets of Pkds and, in the long term, also other kinases implicated in T2D.
By identifying and characterizing the essential signaling networks in liver and adipose tissue the project will contribute to more targeted pharmacological strategies for the treatment of T2D.
Summary
Over 380 million people suffer from diabetes worldwide, with majority of cases being attributed to type 2 diabetes (T2D). Obesity is a major risk factor predisposing to the development of this disease. T2D is characterized by peripheral insulin resistance in combination with relative insulin deficiency that results in hyperglycemia and hyperlipidemia. Liver and adipose tissue are central for regulation of glucose and lipids levels. However, during T2D the hepatic glucose uptake is reduced while rates of gluconeogenesis and lipogenesis are increased. In the adipose tissue, T2D leads to decreased glucose uptake, perturbations in secretion of adipokines and increased lipolysis. Importantly, dysfunction of the liver and the adipose tissue during T2D is caused by defective phosphorylation signaling cascades and normalization of these pathways was shown to attenuate the course of T2D. However, the specific roles of different classes of signaling molecules in these organs remain poorly characterized. We hypothesize that the cross-talk of different classes of signaling molecules determines regulation of metabolism.
Thus, we aim to identify the signaling networks regulating metabolism. The results generated in my own laboratory suggest that the Pkd family kinases are the crucial regulators of metabolic homeostasis. Specifically, Pkd1 and Pkd2 promote obesity and diabetes while Pkd3 controls liver function. Thus, we plan to characterize the molecular mechanisms controlling Pkds signaling. In parallel, we will utilize screening approaches to identify novel, non-canonical signaling modules (phosphatases and components of the ubiquitin system) regulating abundance, localization and phosphorylation of targets of Pkds and, in the long term, also other kinases implicated in T2D.
By identifying and characterizing the essential signaling networks in liver and adipose tissue the project will contribute to more targeted pharmacological strategies for the treatment of T2D.
Max ERC Funding
1 499 128 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym StemProteostasis
Project Mediation of stem cell identity and aging by proteostasis
Researcher (PI) David Vilchez Guerrero
Host Institution (HI) UNIVERSITAET ZU KOELN
Call Details Starting Grant (StG), LS4, ERC-2015-STG
Summary By 2050, the global population over the age of 80 will triple. Thus, research for improving the quality of life at older age can be of enormous benefit for our ever-aging society. To address this challenge we propose an innovative approach based on a combination of stem cell research with genetic experiments in C. elegans. Mechanisms that promote protein homeostasis (proteostasis) slow down aging and decrease the incidence of age-related diseases. Since human embryonic stem cells (hESCs) replicate continuously in the absence of senescence, we hypothesize that they can provide a novel paradigm to study proteostasis and its demise in aging. We have found that hESCs exhibit increased proteasome activity. Moreover, we have uncovered that the proteasome subunit RPN-6 is required for this activity and sufficient to extend healtshpan in C. elegans. However, the mechanisms by which the proteasome regulates hESC function remain unknown. Our first aim is to define how the proteasome regulates not only hESC identity but also aging and the onset of age-related diseases. Moreover, one of the next challenges is to define how other proteostasis pathways impinge upon hESC function. We hypothesize that, in addition to the proteasome, hESCs differentially regulate other subcellular stress response pathways designed to protect them from disequilibrium in the folding and degradation of their proteome. We will perform a comprehensive study of proteostasis of hESCs and mimic this network in somatic cells to alleviate age-related diseases. Finally, we will determine whether loss of proteostasis promotes somatic stem cell (SC) exhaustion, which is one of the most obvious characteristics of the aging process and contributes to tissue degeneration. By using mouse models we will examine whether sustained proteostasis delays neural SC exhaustion. Our research will have an impact in several fields such as stem cell research, neurogenesis, proteostasis, aging and age-related diseases.
Summary
By 2050, the global population over the age of 80 will triple. Thus, research for improving the quality of life at older age can be of enormous benefit for our ever-aging society. To address this challenge we propose an innovative approach based on a combination of stem cell research with genetic experiments in C. elegans. Mechanisms that promote protein homeostasis (proteostasis) slow down aging and decrease the incidence of age-related diseases. Since human embryonic stem cells (hESCs) replicate continuously in the absence of senescence, we hypothesize that they can provide a novel paradigm to study proteostasis and its demise in aging. We have found that hESCs exhibit increased proteasome activity. Moreover, we have uncovered that the proteasome subunit RPN-6 is required for this activity and sufficient to extend healtshpan in C. elegans. However, the mechanisms by which the proteasome regulates hESC function remain unknown. Our first aim is to define how the proteasome regulates not only hESC identity but also aging and the onset of age-related diseases. Moreover, one of the next challenges is to define how other proteostasis pathways impinge upon hESC function. We hypothesize that, in addition to the proteasome, hESCs differentially regulate other subcellular stress response pathways designed to protect them from disequilibrium in the folding and degradation of their proteome. We will perform a comprehensive study of proteostasis of hESCs and mimic this network in somatic cells to alleviate age-related diseases. Finally, we will determine whether loss of proteostasis promotes somatic stem cell (SC) exhaustion, which is one of the most obvious characteristics of the aging process and contributes to tissue degeneration. By using mouse models we will examine whether sustained proteostasis delays neural SC exhaustion. Our research will have an impact in several fields such as stem cell research, neurogenesis, proteostasis, aging and age-related diseases.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
