Project acronym STEMCLOCK
Project Spatiotemporal regulation of epidermal stem cells by circadian rhythms: impact on homeostasis and aging
Researcher (PI) Salvador Aznar Benitah
Host Institution (HI) FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA)
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary "Most adult stem cells are compartmentalized in functionally deterministic niches where they self-renew and maintain homeostasis. From there, stem cells are instructed by combinations of signals and spatial tensile forces which they translate into a specific behavior. However how stem cells spatiotemporally coordinate their stem cell potential with niche- and systemic cues is poorly understood. These issues are essential since perturbations in stem cell function can cause tissue malfunction, such as tumorigenesis and aging.
We propose to perform a systematic analysis to identify the molecular causes that underlie epidermal stem cell aging. We will focus on the interplay between circadian rhythms and stem cell function. The circadian machinery anticipates and synchronizes the daily function of tissues according to the entrainment by natural changes in light and metabolism. We have shown that the molecular clock fine-tunes the behavior of epidermal stem cells by imposing oscillations in the expression of stem cell regulatory genes. These oscillations provide stem cells with a spatiotemporal axis for responding to dormancy, activating, and differentiation cues. Notably, the stem cell clock is naturally dampened upon aging, and forced circadian arrhythmia causes severe epidermal aging and predisposition to tumorigenesis.
We now propose to understand how the circadian clock coordinates the communication between stem cells with local and systemic cues, and how these are perturbed during aging. Specifically we aim: i) To study whether circadian rhythms coordinate the function of niche cells and epidermal stem cells; ii) To identify the molecular causes underlying the age-related dampening of the stem cell clock. We will combine large-scale genomic data, mouse models of circadian arrhythmia, and bioinformatic analysis. We hope to unveil some of the molecular causes underlying the loss of communication between epidermal stem cells and their environment resulting in aging."
Summary
"Most adult stem cells are compartmentalized in functionally deterministic niches where they self-renew and maintain homeostasis. From there, stem cells are instructed by combinations of signals and spatial tensile forces which they translate into a specific behavior. However how stem cells spatiotemporally coordinate their stem cell potential with niche- and systemic cues is poorly understood. These issues are essential since perturbations in stem cell function can cause tissue malfunction, such as tumorigenesis and aging.
We propose to perform a systematic analysis to identify the molecular causes that underlie epidermal stem cell aging. We will focus on the interplay between circadian rhythms and stem cell function. The circadian machinery anticipates and synchronizes the daily function of tissues according to the entrainment by natural changes in light and metabolism. We have shown that the molecular clock fine-tunes the behavior of epidermal stem cells by imposing oscillations in the expression of stem cell regulatory genes. These oscillations provide stem cells with a spatiotemporal axis for responding to dormancy, activating, and differentiation cues. Notably, the stem cell clock is naturally dampened upon aging, and forced circadian arrhythmia causes severe epidermal aging and predisposition to tumorigenesis.
We now propose to understand how the circadian clock coordinates the communication between stem cells with local and systemic cues, and how these are perturbed during aging. Specifically we aim: i) To study whether circadian rhythms coordinate the function of niche cells and epidermal stem cells; ii) To identify the molecular causes underlying the age-related dampening of the stem cell clock. We will combine large-scale genomic data, mouse models of circadian arrhythmia, and bioinformatic analysis. We hope to unveil some of the molecular causes underlying the loss of communication between epidermal stem cells and their environment resulting in aging."
Max ERC Funding
1 495 484 €
Duration
Start date: 2013-01-01, End date: 2017-12-31
Project acronym TARGET GLOMDIS
Project Glomerulonephritis and Focal Segmental Glomerulosclerosis as a Model to Investigate the Link between Inflammation and Kidney Disease:
From Basic Mechanisms to Clinical Application
Researcher (PI) Pierre-Louis Tharaux
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary "Rapidly progressive glomerulonephritis (RPGN) and focal and segmental glomerulosclerosis (FSGS) are severe kidney diseases responsible for irreversible renal failure, which is a major risk factor for mortality. Despite the aggressiveness of immunosuppressive protocols applied, treatments against RPGN have limited effectiveness. Similarly, there is no specific treatment for FSGS. We built this research project on novel identification of molecular pathways and markers of pathogenic glomerular epithelial cells (GEC). Although major roles of endothelial activation with immune-mediated insult and imbalance between coagulation and fibrinolysis have been demonstrated, our findings reinforce this paradigm that “activation” of resident glomerular cells play a key role in disease and extend the concept by examining interactions between surrounding cellular systems. We hypothesize that abnormal activation of G-protein coupled receptors (GPCRs) and EGFR may synergize to switch the phenotype of GECs from healthy to pathological. We propose that coagulation and dysfunction of the capillary barrier, may provide GPCR ligands to receptors present in target cells such as GECs. GPCRs, themselves implicated in GN, are known to transactivate the EGFR. The EGFR has the potential to amplify actions of GPCRs in GECs, leading to cytoskeletal rearrangement, and cell death. We hypothesise that interactions between “switched GECs” and T cells are essential for the perpetuation of the immuno-inflammatory response in such glomerular diseases, after the potentially groundbreaking discovery that lymphocytes display functional EGFR, sensitive to ligands produced by pathological GECs. Finally, we will harness this knowledge for a better identification of patients at risk of glomerular demolition. Our project should identify complementary therapeutic pathways that could then be targeted on top of current immunosuppressive regiments. We also propose that this approach would be beneficial to FSGS."
Summary
"Rapidly progressive glomerulonephritis (RPGN) and focal and segmental glomerulosclerosis (FSGS) are severe kidney diseases responsible for irreversible renal failure, which is a major risk factor for mortality. Despite the aggressiveness of immunosuppressive protocols applied, treatments against RPGN have limited effectiveness. Similarly, there is no specific treatment for FSGS. We built this research project on novel identification of molecular pathways and markers of pathogenic glomerular epithelial cells (GEC). Although major roles of endothelial activation with immune-mediated insult and imbalance between coagulation and fibrinolysis have been demonstrated, our findings reinforce this paradigm that “activation” of resident glomerular cells play a key role in disease and extend the concept by examining interactions between surrounding cellular systems. We hypothesize that abnormal activation of G-protein coupled receptors (GPCRs) and EGFR may synergize to switch the phenotype of GECs from healthy to pathological. We propose that coagulation and dysfunction of the capillary barrier, may provide GPCR ligands to receptors present in target cells such as GECs. GPCRs, themselves implicated in GN, are known to transactivate the EGFR. The EGFR has the potential to amplify actions of GPCRs in GECs, leading to cytoskeletal rearrangement, and cell death. We hypothesise that interactions between “switched GECs” and T cells are essential for the perpetuation of the immuno-inflammatory response in such glomerular diseases, after the potentially groundbreaking discovery that lymphocytes display functional EGFR, sensitive to ligands produced by pathological GECs. Finally, we will harness this knowledge for a better identification of patients at risk of glomerular demolition. Our project should identify complementary therapeutic pathways that could then be targeted on top of current immunosuppressive regiments. We also propose that this approach would be beneficial to FSGS."
Max ERC Funding
1 364 466 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym TMHA
Project Transversal Multilinear Harmonic Analysis
Researcher (PI) Jonathan Bennett
Host Institution (HI) THE UNIVERSITY OF BIRMINGHAM
Call Details Starting Grant (StG), PE1, ERC-2012-StG_20111012
Summary This proposal consists of two intimately related programmes. The aim of Programme 1 is to make major contributions to the celebrated restriction theory for the Fourier transform and combinatorial problems of Kakeya-type using emerging multilinear techniques. The aim of Programme 2 is to develop a multilinear perspective on a much broader family of curvature-related problems in harmonic analysis, including important classes of Radon-like transforms that arise naturally in the theory of dispersive partial differential equations.
The specific objectives represent major challenges at the emerging frontiers of harmonic analysis with a variety of disciplines, including geometric analysis (encompassing heat-flow methods and convex geometry), affine geometry and algebraic topology.
Summary
This proposal consists of two intimately related programmes. The aim of Programme 1 is to make major contributions to the celebrated restriction theory for the Fourier transform and combinatorial problems of Kakeya-type using emerging multilinear techniques. The aim of Programme 2 is to develop a multilinear perspective on a much broader family of curvature-related problems in harmonic analysis, including important classes of Radon-like transforms that arise naturally in the theory of dispersive partial differential equations.
The specific objectives represent major challenges at the emerging frontiers of harmonic analysis with a variety of disciplines, including geometric analysis (encompassing heat-flow methods and convex geometry), affine geometry and algebraic topology.
Max ERC Funding
1 042 293 €
Duration
Start date: 2012-10-01, End date: 2018-09-30
Project acronym TUMORGAN
Project Exploring the tumor as a communicating organ
Researcher (PI) Jan Kristian Pietras
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary The failure to bring about major advances in cancer care over the past decades points to the need for a revolution in our view of cancer as a disease caused by a lack of growth control in malignant cells. We propose that a tumor should be considered a communicating organ made of multiple cell types that collectively evolve into a clinically manifested and deadly disease. With this proposition follows that targeting of communication within tumors to attenuate the support from the stroma is the only viable strategy to achieve long term therapeutic benefit. Our research addresses the need to study the cellular context of cancer with a higher resolution. The general aim of the proposed work is to identify subsets of different cell types within the tumor stroma that hold utility as therapeutic targets and biomarkers. The work will be performed through a set of experiments bridging basic biology, pre-clinical studies and molecular oncology.
The specific aims are:
1) Identification of cellular subsets of the tumor vasculature
2) Investigation of the therapeutic utility of cellular subsets of the tumor vasculature
3) Exploration of the potential of cellular subsets of the tumor vasculature as biomarkers
The aims of the study will be pursued through a series of methodological refinements. Firstly, identification of novel components of tumors will be achieved by the assembly of a mouse genetic tool box enabling isolation, lineage tracing and functional studies. Secondly, single cell transcriptome sequencing will be performed to identify cellular subsets using materials from both mouse and man. Thirdly, the utility as therapeutic targets of the new cellular subsets will be assessed using a live imaging approach. Fourthly, the clinical significance of the new cellular subsets will be investigated using exclusive patient materials.
Taken together, the information provided by our studies will enable us to take cancer therapy into a new era of personalized medicine.
Summary
The failure to bring about major advances in cancer care over the past decades points to the need for a revolution in our view of cancer as a disease caused by a lack of growth control in malignant cells. We propose that a tumor should be considered a communicating organ made of multiple cell types that collectively evolve into a clinically manifested and deadly disease. With this proposition follows that targeting of communication within tumors to attenuate the support from the stroma is the only viable strategy to achieve long term therapeutic benefit. Our research addresses the need to study the cellular context of cancer with a higher resolution. The general aim of the proposed work is to identify subsets of different cell types within the tumor stroma that hold utility as therapeutic targets and biomarkers. The work will be performed through a set of experiments bridging basic biology, pre-clinical studies and molecular oncology.
The specific aims are:
1) Identification of cellular subsets of the tumor vasculature
2) Investigation of the therapeutic utility of cellular subsets of the tumor vasculature
3) Exploration of the potential of cellular subsets of the tumor vasculature as biomarkers
The aims of the study will be pursued through a series of methodological refinements. Firstly, identification of novel components of tumors will be achieved by the assembly of a mouse genetic tool box enabling isolation, lineage tracing and functional studies. Secondly, single cell transcriptome sequencing will be performed to identify cellular subsets using materials from both mouse and man. Thirdly, the utility as therapeutic targets of the new cellular subsets will be assessed using a live imaging approach. Fourthly, the clinical significance of the new cellular subsets will be investigated using exclusive patient materials.
Taken together, the information provided by our studies will enable us to take cancer therapy into a new era of personalized medicine.
Max ERC Funding
1 498 150 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym UB12
Project Ergodic Group Theory
Researcher (PI) Uri Bader
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), PE1, ERC-2012-StG_20111012
Summary "The aim of the proposed research is gaining a better understanding of locally compact groups and their lattices. Our tools are mainly ergodic theoretical.
We propose a variety of novel ideas that open new horizons for research.
The first meta idea is the adoption of tools from the semi-simple theory in order to apply them for general locally compact groups. In particular, we suggest a construction of a ""Weyl group"" and an abstract definition of rank for every locally compact group. We are able to construct a ""Coxeter complex"" and we foresee a construction of a ""building like"" object.
A second set of ideas concerns the category of measure equivalences, which is a natural generalization of the notion of a lattice in a group. This category is long known to be a measurable counterpart of the better studied category of quasi-isometries, yet it misses a good definition of self measure equivalences of an object, analog to the group of quasi-isometries.
We suggest such a definition, and propose to study it, among a variety of related constructions.
A full implementation of our ideas requires a better understanding of locally compact groups.
Thus, an important aspect of the proposed research is that it leaves plenty of room for the study of specific examples and test cases."
Summary
"The aim of the proposed research is gaining a better understanding of locally compact groups and their lattices. Our tools are mainly ergodic theoretical.
We propose a variety of novel ideas that open new horizons for research.
The first meta idea is the adoption of tools from the semi-simple theory in order to apply them for general locally compact groups. In particular, we suggest a construction of a ""Weyl group"" and an abstract definition of rank for every locally compact group. We are able to construct a ""Coxeter complex"" and we foresee a construction of a ""building like"" object.
A second set of ideas concerns the category of measure equivalences, which is a natural generalization of the notion of a lattice in a group. This category is long known to be a measurable counterpart of the better studied category of quasi-isometries, yet it misses a good definition of self measure equivalences of an object, analog to the group of quasi-isometries.
We suggest such a definition, and propose to study it, among a variety of related constructions.
A full implementation of our ideas requires a better understanding of locally compact groups.
Thus, an important aspect of the proposed research is that it leaves plenty of room for the study of specific examples and test cases."
Max ERC Funding
1 150 000 €
Duration
Start date: 2012-09-01, End date: 2018-08-31
Project acronym Universal Banking
Project Universal Banking, Corporate Control and Crises
Researcher (PI) Miguel Luis Sousa De Almeida Ferreira
Host Institution (HI) FACULDADE DE ECONOMIA DA UNIVERSIDADE NOVA DE LISBOA
Call Details Starting Grant (StG), SH1, ERC-2012-StG_20111124
Summary Financial intermediaries play a vital role in providing capital to corporations. The 2007-2009 financial crisis had dramatic consequences on the organization of the financial system that led to the rise of universal banking and financial conglomerates. Financial conglomerates have been common in Europe, but the recent developments have eroded the separation of commercial and investment banking elsewhere. Financial conglomerates act as lenders but also underwrite and trade securities, have equity stakes and sit on the board of corporations, and manage mutual and pension funds that invest in corporations. These forms of corporate control by financial conglomerates are distinct in their incentives and costs and therefore can have distinct effects on non-financial corporations. We will study the effect of control by financial conglomerates on corporation’s performance, investment, financing, and corporate governance policies. A particular relevant channel through which financial conglomerates can affect firm’s policies is the credit channel. Firms establish relationships with financial conglomerates that give easier access to credit and potentially at a lower cost due to economies of scale in information collection and monitoring. There may be, however, costs to firms with a close relationship with a financial conglomerate as firms may be locked up due to an information monopoly. We will study the effects of bank-firm relationships on the loan market. In particular, we will examine the importance of these relationships for explaining differences in the cost of bank distress across firms. The hypothesis is that strong ties with banks reduce firms’ ability to substitute relationship bank loans with other sources of external finance, and therefore firms with stronger relationships could experience greater costs during financial crises. We will contribute to the understanding the consequences of shocks to the financial health of banks for nonfinancial firms.
Summary
Financial intermediaries play a vital role in providing capital to corporations. The 2007-2009 financial crisis had dramatic consequences on the organization of the financial system that led to the rise of universal banking and financial conglomerates. Financial conglomerates have been common in Europe, but the recent developments have eroded the separation of commercial and investment banking elsewhere. Financial conglomerates act as lenders but also underwrite and trade securities, have equity stakes and sit on the board of corporations, and manage mutual and pension funds that invest in corporations. These forms of corporate control by financial conglomerates are distinct in their incentives and costs and therefore can have distinct effects on non-financial corporations. We will study the effect of control by financial conglomerates on corporation’s performance, investment, financing, and corporate governance policies. A particular relevant channel through which financial conglomerates can affect firm’s policies is the credit channel. Firms establish relationships with financial conglomerates that give easier access to credit and potentially at a lower cost due to economies of scale in information collection and monitoring. There may be, however, costs to firms with a close relationship with a financial conglomerate as firms may be locked up due to an information monopoly. We will study the effects of bank-firm relationships on the loan market. In particular, we will examine the importance of these relationships for explaining differences in the cost of bank distress across firms. The hypothesis is that strong ties with banks reduce firms’ ability to substitute relationship bank loans with other sources of external finance, and therefore firms with stronger relationships could experience greater costs during financial crises. We will contribute to the understanding the consequences of shocks to the financial health of banks for nonfinancial firms.
Max ERC Funding
1 174 000 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
