Project acronym CORTEXSELFCONTROL
Project Self-Modulating Neurons in the Cerebral Cortex: From Molecular Mechanisms to Cortical Network Activities
Researcher (PI) Alberto Bacci
Host Institution (HI) INSTITUT DU CERVEAU ET DE LA MOELLE EPINIERE
Call Details Starting Grant (StG), LS4, ERC-2007-StG
Summary In the mammalian brain, the neocortex is the site where sensory information is integrated into complex cognitive functions. This is accomplished by the activity of both principal glutamatergic neurons and locally-projecting inhibitory GABAergic interneurons, interconnected in complex networks. Inhibitory neurons play several key roles in neocortical function. For example, they shape sensory receptive fields and drive several high frequency network oscillations. On the other hand, defects in their function can lead to devastating diseases, such as epilepsy and schizophrenia. Cortical interneurons represent a highly heterogeneous cell population. Understanding the specific role of each interneuron subtype within cortical microcircuits is still a crucial open question. We have examined properties of two major functional interneuron subclasses in neocortical layer V: fast-spiking (FS) and low-threshold spiking (LTS) cells. Our previous data indicate that each group expresses a novel form of self inhibition, namely autaptic inhibitory transmission in FS cells and an endocannabinoid-mediated slow self inhibition in LTS interneurons. In this proposal we will address three major questions relevant to self-inhibition of neocortical interneurons: 1) What is the role of FS cell autapses in coordinating fast network synchrony? 2) What are the molecular mechanisms underlying autaptic asynchronous release, prolonging FS cell self-inhibition by several seconds, and what is its relevance during physiological and pathological network activities? 3) What are the induction mechanisms, the molecular players involved and the functional roles within cortical microcircuits of the endocannabinoid-mediated long-lasting self-inhibition in LTS interneurons? Results of these experiments will lead to a better understanding of GABAergic interneuron regulation of neocortical excitability, relevant to both normal and pathological cortical function.
Summary
In the mammalian brain, the neocortex is the site where sensory information is integrated into complex cognitive functions. This is accomplished by the activity of both principal glutamatergic neurons and locally-projecting inhibitory GABAergic interneurons, interconnected in complex networks. Inhibitory neurons play several key roles in neocortical function. For example, they shape sensory receptive fields and drive several high frequency network oscillations. On the other hand, defects in their function can lead to devastating diseases, such as epilepsy and schizophrenia. Cortical interneurons represent a highly heterogeneous cell population. Understanding the specific role of each interneuron subtype within cortical microcircuits is still a crucial open question. We have examined properties of two major functional interneuron subclasses in neocortical layer V: fast-spiking (FS) and low-threshold spiking (LTS) cells. Our previous data indicate that each group expresses a novel form of self inhibition, namely autaptic inhibitory transmission in FS cells and an endocannabinoid-mediated slow self inhibition in LTS interneurons. In this proposal we will address three major questions relevant to self-inhibition of neocortical interneurons: 1) What is the role of FS cell autapses in coordinating fast network synchrony? 2) What are the molecular mechanisms underlying autaptic asynchronous release, prolonging FS cell self-inhibition by several seconds, and what is its relevance during physiological and pathological network activities? 3) What are the induction mechanisms, the molecular players involved and the functional roles within cortical microcircuits of the endocannabinoid-mediated long-lasting self-inhibition in LTS interneurons? Results of these experiments will lead to a better understanding of GABAergic interneuron regulation of neocortical excitability, relevant to both normal and pathological cortical function.
Max ERC Funding
996 000 €
Duration
Start date: 2008-10-01, End date: 2014-03-31
Project acronym CRCStemCellDynamics
Project Molecular Subtype Specific Stem Cell Dynamics in Developing and Established Colorectal Cancers
Researcher (PI) Louis Vermeulen
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Call Details Starting Grant (StG), LS4, ERC-2014-STG
Summary Annually 1.2 million new cases of colorectal cancer (CRC) are seen worldwide and over 50% of patients die of the disease making it a leading cause of cancer-related mortality. A crucial contributing factor to these disappointing figures is that CRC is a heterogeneous disease and tumours differ extensively in the clinical presentation and response to therapy. Recent unsupervised classification studies highlight that only a proportion of this heterogeneity can be explained by the variation in commonly found (epi-)genetic aberrations. Hence the origins of CRC heterogeneity remain poorly understood.
The central hypothesis of this research project is that the cell of origin contributes to the phenotype and functional properties of the pre-malignant clone and the resulting malignancy. To study this concept I will generate cell of origin- and mutation-specific molecular profiles of oncogenic clones and relate those to human CRC samples. Furthermore, I will quantitatively investigate how mutations and the cell of origin act in concert to determine the functional characteristics of the pre-malignant clone that ultimately develops into an invasive intestinal tumour. These studies are paralleled by the investigation of stem cell dynamics within established human CRCs by means of a novel marker independent lineage tracing strategy in combination with mathematical analysis techniques. This will provide critical and quantitative information on the relevance of the cancer stem cell concept in CRC and on the degree of inter-tumour variation with respect to the frequency and functional features of stem-like cells within individual CRCs and molecular subtypes of the disease.
I am convinced that a better and quantitative understanding of the dynamical properties of stem cells during tumour development and within established CRCs will be pivotal for an improved classification, prevention and treatment of CRC.
Summary
Annually 1.2 million new cases of colorectal cancer (CRC) are seen worldwide and over 50% of patients die of the disease making it a leading cause of cancer-related mortality. A crucial contributing factor to these disappointing figures is that CRC is a heterogeneous disease and tumours differ extensively in the clinical presentation and response to therapy. Recent unsupervised classification studies highlight that only a proportion of this heterogeneity can be explained by the variation in commonly found (epi-)genetic aberrations. Hence the origins of CRC heterogeneity remain poorly understood.
The central hypothesis of this research project is that the cell of origin contributes to the phenotype and functional properties of the pre-malignant clone and the resulting malignancy. To study this concept I will generate cell of origin- and mutation-specific molecular profiles of oncogenic clones and relate those to human CRC samples. Furthermore, I will quantitatively investigate how mutations and the cell of origin act in concert to determine the functional characteristics of the pre-malignant clone that ultimately develops into an invasive intestinal tumour. These studies are paralleled by the investigation of stem cell dynamics within established human CRCs by means of a novel marker independent lineage tracing strategy in combination with mathematical analysis techniques. This will provide critical and quantitative information on the relevance of the cancer stem cell concept in CRC and on the degree of inter-tumour variation with respect to the frequency and functional features of stem-like cells within individual CRCs and molecular subtypes of the disease.
I am convinced that a better and quantitative understanding of the dynamical properties of stem cells during tumour development and within established CRCs will be pivotal for an improved classification, prevention and treatment of CRC.
Max ERC Funding
1 499 875 €
Duration
Start date: 2015-04-01, End date: 2021-03-31
Project acronym CSI-Fun
Project Chronic Systemic Inflammation: Functional organ cross-talk in inflammatory disease and cancer
Researcher (PI) Erwin Friedrich WAGNER
Host Institution (HI) MEDIZINISCHE UNIVERSITAET WIEN
Call Details Advanced Grant (AdG), LS4, ERC-2016-ADG
Summary Chronic Systemic Inflammation (CSI) resulting from systemic release of inflammatory cytokines and activation of the immune system is responsible for the progression of several debilitating diseases, such as Psoriasis, Arthritis and Cancer. Initially localised diseases can result in CSI with subsequent systemic spread to distant organs, a key patho-physiological phase responsible for major morbidity and even mortality. Despite the importance of CSI, a complete understanding of the molecular mechanisms, signalling pathways and cell types involved, as well as the chronological evolution of the systemic inflammatory response is still elusive. The classical approach to study inflammation has focused on investigating individual cell types or organs in the pathogenesis of a single disease, thereby neglecting important organ cross-talk and systemic interactions. Furthermore, understanding the temporal and spatial kinetics modulating the inflammatory response requires a detailed study of interactions between different immune and non-immune organs at various time points during disease progression in the context of the whole organism.
The aim of this research proposal is to substantially advance our understanding of whole organ physiology in relation to systemic inflammation as a cause or/and consequence of disease with the focus on Psoriasis/Joint Diseases and Cancer Cachexia. The goal is to elucidate the molecular mechanisms at the cellular and systemic level, and to decipher endocrine interactions and cross-talks between distant organs. Various model systems ranging from cell cultures to genetically engineered mouse models to human clinical samples will be employed. Genomic, proteomic and metabolomic data will be combined with functional in vivo assessment using mouse models to understand the multi-faceted role of systemic inflammation in chronic human diseases, such as Inflammatory Skin/Joint disease and Cachexia, a deadly systemic manifestation of Cancer.
Summary
Chronic Systemic Inflammation (CSI) resulting from systemic release of inflammatory cytokines and activation of the immune system is responsible for the progression of several debilitating diseases, such as Psoriasis, Arthritis and Cancer. Initially localised diseases can result in CSI with subsequent systemic spread to distant organs, a key patho-physiological phase responsible for major morbidity and even mortality. Despite the importance of CSI, a complete understanding of the molecular mechanisms, signalling pathways and cell types involved, as well as the chronological evolution of the systemic inflammatory response is still elusive. The classical approach to study inflammation has focused on investigating individual cell types or organs in the pathogenesis of a single disease, thereby neglecting important organ cross-talk and systemic interactions. Furthermore, understanding the temporal and spatial kinetics modulating the inflammatory response requires a detailed study of interactions between different immune and non-immune organs at various time points during disease progression in the context of the whole organism.
The aim of this research proposal is to substantially advance our understanding of whole organ physiology in relation to systemic inflammation as a cause or/and consequence of disease with the focus on Psoriasis/Joint Diseases and Cancer Cachexia. The goal is to elucidate the molecular mechanisms at the cellular and systemic level, and to decipher endocrine interactions and cross-talks between distant organs. Various model systems ranging from cell cultures to genetically engineered mouse models to human clinical samples will be employed. Genomic, proteomic and metabolomic data will be combined with functional in vivo assessment using mouse models to understand the multi-faceted role of systemic inflammation in chronic human diseases, such as Inflammatory Skin/Joint disease and Cachexia, a deadly systemic manifestation of Cancer.
Max ERC Funding
2 499 875 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym Ctrl-BBB
Project Blood-brain barrier: from molecular mechanisms to intervention strategies
Researcher (PI) Benoit VANHOLLEBEKE
Host Institution (HI) UNIVERSITE LIBRE DE BRUXELLES
Call Details Consolidator Grant (CoG), LS4, ERC-2019-COG
Summary Brain endothelial cells (ECs) are endowed with a set of molecular and metabolic adaptations that stringently orchestrate the molecular and cellular transit between the brain and the circulatory system. These adaptations constitute the blood-brain barrier (BBB) and are pivotal to brain homeostasis and protection. Accordingly, BBB dysfunction is a unifying hallmark of many cerebrovascular diseases, including stroke, multiple sclerosis and neurodegeneration. Healing the BBB to treat to the brain is therefore emerging as a powerful therapeutic avenue for a spectrum of human CNS disorders. In addition, through its neuroprotective function, the BBB represents the main obstacle for CNS drug delivery. There is consequently an urgent need to identify methods to control BBB in health and disease. Of pivotal importance, BBB is not genetically hardwired, but instead results from ongoing neurovascular communications taking place between the ECs and the other components of the neurovascular unit. Shedding light on these communications, and raising our understanding to the mechanistic level will undoubtedly yield transformative therapeutic strategies for human brain disorders. A key obstacle in the study of BBB permeability resides in its complex regulation across cells and tissues. This complexity cannot be recapitulated in cell culture experiments. Our laboratory has recently identified and validated the transparent zebrafish as ideally suited to facilitate these studies, by empowering non-invasive genetic analyses of BBB function under normoxia. Together with a conserved BBB genetic instruction program, the zebrafish cerebrovasculature qualifies as a an alternative “miniature BBB model” where neurovascular communication can be studied at an unprecedented pace. Ctrl-BBB will pioneer synergistic approaches between the zebrafish and the mouse model, to bring BBB research in the era of highly parallel genetic approaches and BBB-focused therapeutic strategies for brain disorders.
Summary
Brain endothelial cells (ECs) are endowed with a set of molecular and metabolic adaptations that stringently orchestrate the molecular and cellular transit between the brain and the circulatory system. These adaptations constitute the blood-brain barrier (BBB) and are pivotal to brain homeostasis and protection. Accordingly, BBB dysfunction is a unifying hallmark of many cerebrovascular diseases, including stroke, multiple sclerosis and neurodegeneration. Healing the BBB to treat to the brain is therefore emerging as a powerful therapeutic avenue for a spectrum of human CNS disorders. In addition, through its neuroprotective function, the BBB represents the main obstacle for CNS drug delivery. There is consequently an urgent need to identify methods to control BBB in health and disease. Of pivotal importance, BBB is not genetically hardwired, but instead results from ongoing neurovascular communications taking place between the ECs and the other components of the neurovascular unit. Shedding light on these communications, and raising our understanding to the mechanistic level will undoubtedly yield transformative therapeutic strategies for human brain disorders. A key obstacle in the study of BBB permeability resides in its complex regulation across cells and tissues. This complexity cannot be recapitulated in cell culture experiments. Our laboratory has recently identified and validated the transparent zebrafish as ideally suited to facilitate these studies, by empowering non-invasive genetic analyses of BBB function under normoxia. Together with a conserved BBB genetic instruction program, the zebrafish cerebrovasculature qualifies as a an alternative “miniature BBB model” where neurovascular communication can be studied at an unprecedented pace. Ctrl-BBB will pioneer synergistic approaches between the zebrafish and the mouse model, to bring BBB research in the era of highly parallel genetic approaches and BBB-focused therapeutic strategies for brain disorders.
Max ERC Funding
2 286 543 €
Duration
Start date: 2020-10-01, End date: 2025-09-30
Project acronym CuRE
Project Cardiac REgeneration from within
Researcher (PI) Mauro GIACCA
Host Institution (HI) KING'S COLLEGE LONDON
Call Details Advanced Grant (AdG), LS4, ERC-2017-ADG
Summary Biotechnological therapies for patients with myocardial infarction and heart failure are urgently needed, in light of the breadth of these diseases and a lack of curative treatments. CuRE is an ambitious project aimed at identifying novel factors (cytokines, growth factors, microRNAs) that promote cardiomyocyte proliferation and can thus be transformed into innovative therapeutics to stimulate cardiac regeneration. The Project leads from two concepts: first, that cardiac regeneration can be obtained by stimulating the endogenous capacity of cardiomyocytes to proliferate, second that effective biotherapeutics might be identified through systematic screenings both in vivo and ex vivo. In the mouse, CuRE will take advantage of two unique arrayed libraries cloned in adeno-associated virus (AAV) vectors, one corresponding to the secretome (1200 factors) and the other to the miRNAome (800 pri-miRNA genes). Both libraries will be functionally screened in mice to search for factors that enhance cardiac regeneration. This in vivo selection approach will be complemented by a series of high throughput screenings on primary cardiomyocytes ex vivo, aimed at systematically assessing the involvement of all components of the ubiquitin/proteasome pathway, the cytoskeleton and the sarcomere on cell proliferation. Cytokines and miRNAs can both be developed to become therapeutic molecules, in the form of recombinant proteins and synthetic nucleic acids, respectively. Therefore, a key aim of CuRE will be to establish procedures for their production and administration in vivo, and to assess their efficacy in both small and large animal models of myocardial damage. In addition to this translational goal, the project will entail the successful achievement of several intermediate objectives, each of which possesses intrinsic validity in terms of basic discovery and is thus expected to extend technology and knowledge in the cardiovascular field beyond state-of-the art.
Summary
Biotechnological therapies for patients with myocardial infarction and heart failure are urgently needed, in light of the breadth of these diseases and a lack of curative treatments. CuRE is an ambitious project aimed at identifying novel factors (cytokines, growth factors, microRNAs) that promote cardiomyocyte proliferation and can thus be transformed into innovative therapeutics to stimulate cardiac regeneration. The Project leads from two concepts: first, that cardiac regeneration can be obtained by stimulating the endogenous capacity of cardiomyocytes to proliferate, second that effective biotherapeutics might be identified through systematic screenings both in vivo and ex vivo. In the mouse, CuRE will take advantage of two unique arrayed libraries cloned in adeno-associated virus (AAV) vectors, one corresponding to the secretome (1200 factors) and the other to the miRNAome (800 pri-miRNA genes). Both libraries will be functionally screened in mice to search for factors that enhance cardiac regeneration. This in vivo selection approach will be complemented by a series of high throughput screenings on primary cardiomyocytes ex vivo, aimed at systematically assessing the involvement of all components of the ubiquitin/proteasome pathway, the cytoskeleton and the sarcomere on cell proliferation. Cytokines and miRNAs can both be developed to become therapeutic molecules, in the form of recombinant proteins and synthetic nucleic acids, respectively. Therefore, a key aim of CuRE will be to establish procedures for their production and administration in vivo, and to assess their efficacy in both small and large animal models of myocardial damage. In addition to this translational goal, the project will entail the successful achievement of several intermediate objectives, each of which possesses intrinsic validity in terms of basic discovery and is thus expected to extend technology and knowledge in the cardiovascular field beyond state-of-the art.
Max ERC Funding
2 428 492 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym cureCD
Project Function of long non-coding RNA in Crohn Disease Ulcer Pathogenesis
Researcher (PI) Yael HABERMAN ZIV
Host Institution (HI) MEDICAL RESEARCH INFRASTRUCTURE DEVELOPMENT AND HEALTH SERVICES FUND BY THE SHEBA MEDICAL CENTER
Call Details Starting Grant (StG), LS4, ERC-2017-STG
Summary The Inflammatory Bowel Diseases (IBD), Crohn’s Disease (CD) and Ulcerative Colitis (UC) are chronic/relapsing disorders that affect over six million individuals worldwide. Mucosal ulcers, the hallmark of CD, are the result of a complex interaction between microbiota, immune cells, and gut epithelia. Healing of mucosal ulcers is associated with better outcomes, but is achieved in less than half of cases. Past attempts to suppress central and conserved nodes of the immune system failed due to opposing off-target deleterious effects on epithelial renewal. Therefore, there is a critical need to identify more tissue specific targets that lead to mucosal healing and to improved outcomes.
Using mRNAseq of intestinal biopsies, we identified a widespread dysregulation of long non-coding RNAs (lncRNA) in the ileum of treatment naïve pediatric CD patients. Importently, we identified significant correlations between lncRNA and mucosal ulcers. CD lncRNA, after carful mechanistic exploration, are highly promising targets for potential future intervention as they regulate diverse cellular functions and exhibit a more tissue specific expression in comparison to protein coding genes. The core goal of this proposal is to understand the role of CD lncRNA in ulcer pathogenesis focusing on granulocytes and epithelial functions in the contexts of their interactions with the microbiota.
I plan to utilize state of the art informatics, RNAseq and microbiome profiles together with advanced and novel experimental lab model and co-culture systems, patients-derived prospectively collected tissues, and gut microbiota to explore the role of CD lncRNA function in mediating healing of mucosal ulcers. This work carries the potential to guide new novel therapeutic strategies for mucosal healing with minimal off-targets effects. In a broader prospective, this work will expand our relative limited understanding regarding the role of lncRNA in mediating human diseases.
Summary
The Inflammatory Bowel Diseases (IBD), Crohn’s Disease (CD) and Ulcerative Colitis (UC) are chronic/relapsing disorders that affect over six million individuals worldwide. Mucosal ulcers, the hallmark of CD, are the result of a complex interaction between microbiota, immune cells, and gut epithelia. Healing of mucosal ulcers is associated with better outcomes, but is achieved in less than half of cases. Past attempts to suppress central and conserved nodes of the immune system failed due to opposing off-target deleterious effects on epithelial renewal. Therefore, there is a critical need to identify more tissue specific targets that lead to mucosal healing and to improved outcomes.
Using mRNAseq of intestinal biopsies, we identified a widespread dysregulation of long non-coding RNAs (lncRNA) in the ileum of treatment naïve pediatric CD patients. Importently, we identified significant correlations between lncRNA and mucosal ulcers. CD lncRNA, after carful mechanistic exploration, are highly promising targets for potential future intervention as they regulate diverse cellular functions and exhibit a more tissue specific expression in comparison to protein coding genes. The core goal of this proposal is to understand the role of CD lncRNA in ulcer pathogenesis focusing on granulocytes and epithelial functions in the contexts of their interactions with the microbiota.
I plan to utilize state of the art informatics, RNAseq and microbiome profiles together with advanced and novel experimental lab model and co-culture systems, patients-derived prospectively collected tissues, and gut microbiota to explore the role of CD lncRNA function in mediating healing of mucosal ulcers. This work carries the potential to guide new novel therapeutic strategies for mucosal healing with minimal off-targets effects. In a broader prospective, this work will expand our relative limited understanding regarding the role of lncRNA in mediating human diseases.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
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 CYTOVOLION
Project Ion homeostasis and volume regulation of cells and organelles
Researcher (PI) Thomas Jürgen Jentsch
Host Institution (HI) FORSCHUNGSVERBUND BERLIN EV
Call Details Advanced Grant (AdG), LS4, ERC-2011-ADG_20110310
Summary The regulation of ion concentrations in the cytoplasm and in the lumen of intracellular vesicles provides suitable environments for biochemical reactions, gradients for signal transduction, and generates osmotic gradients for the regulation of the volume of cells and intracellular organelles. Changes in the ion homeostasis and volume of cells and organelles may in turn influence processes like cell division and migration or the budding of vesicles from cellular membranes. Volume changes of cells, and possibly also of intracellular organelles, in turn regulate ion transport across their membranes. Whereas several swelling-activated plasma membrane ion transporters and channels are known, the molecular identity of a key player, the swelling-activated anion channel VRAC, and its impact on cellular functions remain elusive. Only sketchy information is available on ion homeostasis and volume regulation of intracellular organelles like endosomes and lysosomes, in spite of their importance for several diseases.
We propose to perform a genome-wide RNAi screen to finally identify the long-sought swelling-activated Cl- channel VRAC at the molecular level. This screen will also identify genes involved in the regulation of VRAC. The network involved in cell volume regulation will be investigated at the structural, biochemical and cellular level as well as with genetically modified mice. In parallel we will examine the ion homeostasis of endosomes and lysosomes. Until recently only the regulation of luminal H+ and Ca++ concentration was studied, but our recent work demonstrated a crucial role of luminal Cl- and hinted at an important role of cations. A combination of proteomics, siRNA screens, candidate approaches, and mouse models will be used to elucidate the ion homeostasis of endosomes/lysosomes and the impact on organellar function and associated pathologies. We expect that our work will break new ground in ion transport physiology, pathology, and cell biology.
Summary
The regulation of ion concentrations in the cytoplasm and in the lumen of intracellular vesicles provides suitable environments for biochemical reactions, gradients for signal transduction, and generates osmotic gradients for the regulation of the volume of cells and intracellular organelles. Changes in the ion homeostasis and volume of cells and organelles may in turn influence processes like cell division and migration or the budding of vesicles from cellular membranes. Volume changes of cells, and possibly also of intracellular organelles, in turn regulate ion transport across their membranes. Whereas several swelling-activated plasma membrane ion transporters and channels are known, the molecular identity of a key player, the swelling-activated anion channel VRAC, and its impact on cellular functions remain elusive. Only sketchy information is available on ion homeostasis and volume regulation of intracellular organelles like endosomes and lysosomes, in spite of their importance for several diseases.
We propose to perform a genome-wide RNAi screen to finally identify the long-sought swelling-activated Cl- channel VRAC at the molecular level. This screen will also identify genes involved in the regulation of VRAC. The network involved in cell volume regulation will be investigated at the structural, biochemical and cellular level as well as with genetically modified mice. In parallel we will examine the ion homeostasis of endosomes and lysosomes. Until recently only the regulation of luminal H+ and Ca++ concentration was studied, but our recent work demonstrated a crucial role of luminal Cl- and hinted at an important role of cations. A combination of proteomics, siRNA screens, candidate approaches, and mouse models will be used to elucidate the ion homeostasis of endosomes/lysosomes and the impact on organellar function and associated pathologies. We expect that our work will break new ground in ion transport physiology, pathology, and cell biology.
Max ERC Funding
2 499 600 €
Duration
Start date: 2012-04-01, End date: 2017-03-31
Project acronym Damocles
Project Modelling brain aneurysm to elucidate the role of platelets
Researcher (PI) Yacine BOULAFTALI
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS4, ERC-2017-STG
Summary In the European Union, 15 million people have an unruptured intracranial aneurysm (IA) that may rupture one day and lead to subarachnoid haemorrhage (SAH). The IA rupture event is ominous and lingers as a clinical quandary. No safe and effective non-invasive therapies have, as of yet, been identified and implemented in clinical practice mainly because of a lack of knowledge of the underlying mechanisms. Increasing evidence points to inflammation as one of the leading factors in the pathogenesis of IA. Intrasaccular clot formation is a common feature of IA occurring unruptured and ruptured IA. In addition to forming clots, activated platelets support leukocyte recruitment. Interestingly, platelets also prevent local hemorrhage in inflammatory situations independently of their ability to form a platelet plug.
We hypothesize that the role of platelet may evolve throughout the development of IA: initially playing a protective role of in the maintenance of vascular integrity in response to inflammation and contributing later to intrasaccular thrombus formation. What are the platelet signaling pathways and responses involved and to what extent do they contribute to the disease and the rupture event?
To answer these questions, we designed an interdisciplinary proposal, which gathers biophysical, pharmacological, and in-vivo approaches, with the following objectives: I) To investigate platelet functions from patients diagnosed with intracranial aneurysm at the sites of aneurysm sac. II) To delineate platelet mechanisms and responses in a cutting-edge technology of a 3D reconstruction of IA that will take into account the hemodynamic shear stress. III) To test in a preclinical mouse model of IA efficient anti-platelet therapies and define a therapeutic window to intervene on platelet activation. The proposed project will yield new insights in IA disease and in life science, from cell biology to the discovery of potential new targets in cardiovascular medicine.
Summary
In the European Union, 15 million people have an unruptured intracranial aneurysm (IA) that may rupture one day and lead to subarachnoid haemorrhage (SAH). The IA rupture event is ominous and lingers as a clinical quandary. No safe and effective non-invasive therapies have, as of yet, been identified and implemented in clinical practice mainly because of a lack of knowledge of the underlying mechanisms. Increasing evidence points to inflammation as one of the leading factors in the pathogenesis of IA. Intrasaccular clot formation is a common feature of IA occurring unruptured and ruptured IA. In addition to forming clots, activated platelets support leukocyte recruitment. Interestingly, platelets also prevent local hemorrhage in inflammatory situations independently of their ability to form a platelet plug.
We hypothesize that the role of platelet may evolve throughout the development of IA: initially playing a protective role of in the maintenance of vascular integrity in response to inflammation and contributing later to intrasaccular thrombus formation. What are the platelet signaling pathways and responses involved and to what extent do they contribute to the disease and the rupture event?
To answer these questions, we designed an interdisciplinary proposal, which gathers biophysical, pharmacological, and in-vivo approaches, with the following objectives: I) To investigate platelet functions from patients diagnosed with intracranial aneurysm at the sites of aneurysm sac. II) To delineate platelet mechanisms and responses in a cutting-edge technology of a 3D reconstruction of IA that will take into account the hemodynamic shear stress. III) To test in a preclinical mouse model of IA efficient anti-platelet therapies and define a therapeutic window to intervene on platelet activation. The proposed project will yield new insights in IA disease and in life science, from cell biology to the discovery of potential new targets in cardiovascular medicine.
Max ERC Funding
1 498 618 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym DeAge
Project Deconstructing Ageing: from molecular mechanisms to intervention strategies
Researcher (PI) Carlos LOPEZ OTIN
Host Institution (HI) UNIVERSIDAD DE OVIEDO
Call Details Advanced Grant (AdG), LS4, ERC-2016-ADG
Summary Over many years, our research group has explored the complex relationship between cancer and ageing. As part of this work, we have generated mouse models of protease deficiency which are protected from cancer but exhibit accelerated ageing. Further studies with these mice have allowed us to unveil novel mechanisms of both normal and pathological ageing, to discover two new human progeroid syndromes, and to develop therapies for the Hutchinson-Gilford progeria syndrome, now in clinical trials. We have also integrated data from many laboratories to first define The hallmarks of ageing and the current possibilities for Metabolic control of longevity. Now, we propose to leverage our extensive experience in this field to further explore the relative relevance of cell-intrinsic and -extrinsic mechanisms of ageing. Our central hypothesis is that ageing derives from the combination of both systemic and cell-autonomous deficiencies which lead to the characteristic loss of fitness associated with this process. Accordingly, it is necessary to integrate multiple approaches to understand the mechanisms underlying ageing. This integrative and multidisciplinary project is organized around three major aims: 1) to characterize critical cell-intrinsic alterations which drive ageing; 2) to investigate ageing as a systemic process; and 3) to design intervention strategies aimed at expanding longevity. To fully address these objectives, we will use both hypothesis-driven and unbiased approaches, including next-generation sequencing, genome editing, and cell reprogramming. We will also perform in vivo experiments with mouse models of premature ageing, genomic and metagenomic studies with short- and long-lived organisms, and functional analyses with human samples from both progeria patients and centenarians. The information derived from this project will provide new insights into the molecular mechanisms of ageing and may lead to discover new opportunities to extend human healthspan.
Summary
Over many years, our research group has explored the complex relationship between cancer and ageing. As part of this work, we have generated mouse models of protease deficiency which are protected from cancer but exhibit accelerated ageing. Further studies with these mice have allowed us to unveil novel mechanisms of both normal and pathological ageing, to discover two new human progeroid syndromes, and to develop therapies for the Hutchinson-Gilford progeria syndrome, now in clinical trials. We have also integrated data from many laboratories to first define The hallmarks of ageing and the current possibilities for Metabolic control of longevity. Now, we propose to leverage our extensive experience in this field to further explore the relative relevance of cell-intrinsic and -extrinsic mechanisms of ageing. Our central hypothesis is that ageing derives from the combination of both systemic and cell-autonomous deficiencies which lead to the characteristic loss of fitness associated with this process. Accordingly, it is necessary to integrate multiple approaches to understand the mechanisms underlying ageing. This integrative and multidisciplinary project is organized around three major aims: 1) to characterize critical cell-intrinsic alterations which drive ageing; 2) to investigate ageing as a systemic process; and 3) to design intervention strategies aimed at expanding longevity. To fully address these objectives, we will use both hypothesis-driven and unbiased approaches, including next-generation sequencing, genome editing, and cell reprogramming. We will also perform in vivo experiments with mouse models of premature ageing, genomic and metagenomic studies with short- and long-lived organisms, and functional analyses with human samples from both progeria patients and centenarians. The information derived from this project will provide new insights into the molecular mechanisms of ageing and may lead to discover new opportunities to extend human healthspan.
Max ERC Funding
2 456 250 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
