Project acronym CaNANObinoids
Project From Peripheralized to Cell- and Organelle-Targeted Medicine: The 3rd Generation of Cannabinoid-1 Receptor Antagonists for the Treatment of Chronic Kidney Disease
Researcher (PI) Yossef Tam
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS4, ERC-2015-STG
Summary Clinical experience with globally-acting cannabinoid-1 receptor (CB1R) antagonists revealed the benefits of blocking CB1Rs for the treatment of obesity and diabetes. However, their use is hampered by increased CNS-mediated side effects. Recently, I have demonstrated that peripherally-restricted CB1R antagonists have the potential to treat the metabolic syndrome without eliciting these adverse effects. While these results are promising and are currently being developed into the clinic, our ability to rationally design CB1R blockers that would target a diseased organ is limited.
The current proposal aims to develop and test cell- and organelle-specific CB1R antagonists. To establish this paradigm, I will focus our interest on the kidney, since chronic kidney disease (CKD) is the leading cause of increased morbidity and mortality of patients with diabetes. Our first goal will be to characterize the obligatory role of the renal proximal tubular CB1R in the pathogenesis of diabetic renal complications. Next, we will attempt to link renal proximal CB1R with diabetic mitochondrial dysfunction. Finally, we will develop proximal tubular (cell-specific) and mitochondrial (organelle-specific) CB1R blockers and test their effectiveness in treating CKD. To that end, we will encapsulate CB1R blockers into biocompatible polymeric nanoparticles that will serve as targeted drug delivery systems, via their conjugation to targeting ligands.
The implications of this work are far reaching as they will (i) point to renal proximal tubule CB1R as a novel target for CKD; (ii) identify mitochondrial CB1R as a new player in the regulation of proximal tubular cell function, and (iii) eventually become the drug-of-choice in treating diabetic CKD and its comorbidities. Moreover, this work will lead to the development of a novel organ-specific drug delivery system for CB1R blockers, which could be then exploited in other tissues affected by obesity, diabetes and the metabolic syndrome.
Summary
Clinical experience with globally-acting cannabinoid-1 receptor (CB1R) antagonists revealed the benefits of blocking CB1Rs for the treatment of obesity and diabetes. However, their use is hampered by increased CNS-mediated side effects. Recently, I have demonstrated that peripherally-restricted CB1R antagonists have the potential to treat the metabolic syndrome without eliciting these adverse effects. While these results are promising and are currently being developed into the clinic, our ability to rationally design CB1R blockers that would target a diseased organ is limited.
The current proposal aims to develop and test cell- and organelle-specific CB1R antagonists. To establish this paradigm, I will focus our interest on the kidney, since chronic kidney disease (CKD) is the leading cause of increased morbidity and mortality of patients with diabetes. Our first goal will be to characterize the obligatory role of the renal proximal tubular CB1R in the pathogenesis of diabetic renal complications. Next, we will attempt to link renal proximal CB1R with diabetic mitochondrial dysfunction. Finally, we will develop proximal tubular (cell-specific) and mitochondrial (organelle-specific) CB1R blockers and test their effectiveness in treating CKD. To that end, we will encapsulate CB1R blockers into biocompatible polymeric nanoparticles that will serve as targeted drug delivery systems, via their conjugation to targeting ligands.
The implications of this work are far reaching as they will (i) point to renal proximal tubule CB1R as a novel target for CKD; (ii) identify mitochondrial CB1R as a new player in the regulation of proximal tubular cell function, and (iii) eventually become the drug-of-choice in treating diabetic CKD and its comorbidities. Moreover, this work will lead to the development of a novel organ-specific drug delivery system for CB1R blockers, which could be then exploited in other tissues affected by obesity, diabetes and the metabolic syndrome.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym CD40-INN
Project CD40 goes innate: defining and targeting CD40 signaling intermediates in the macrophage to treat atherosclerosis
Researcher (PI) Esther Lutgens Leiner
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Call Details Consolidator Grant (CoG), LS4, ERC-2015-CoG
Summary Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVD), is a lipid driven, inflammatory disease of the large arteries. Despite a 25% relative risk reduction achieved by lipid-lowering treatment, the vast majority of atherosclerosis-induced CVD risk remains unaddressed. Therefore, characterizing mediators of the inflammatory aspect of atherosclerosis is a widely recognized scientific goal with great therapeutic implications.
Co-stimulatory molecules are key players in modulating immune interactions. My laboratory has defined the co-stimulatory CD40-CD40L dyad as a major driver of atherosclerosis. Inhibition of CD40, and of its interaction with the adaptor molecule TRAF6 by genetic deficiency, antibody treatment or (nanoparticle based) small molecule inhibitor (SMI) treatment, is one of the most powerful therapies to reduce atherosclerosis in a laboratory setting. Although CD40-CD40L interactions are associated with adaptive immunity, I recently identified the macrophage as a driver of CD40-induced inflammation in atherosclerosis. We will use state-of-the-art in vitro experiments, live cell-, super resolution imaging, proteomics approaches and mutant mouse models to unravel the role of macrophage CD40 in atherosclerosis. Moreover, using structure based virtual ligand screening, I will develop lead SMIs targeting macrophage CD40-signaling, which I will deliver using macrophage-targeting nanoparticles. My goal is to define the role of macrophage CD40 in inflammation and immunity and disentangle how its activation affects atherosclerosis. I will finally test the feasibility of targeting macrophage CD40-signaling as a treatment for CVD.
These studies will define the role of CD40-signaling in the innate immune system in health and (cardiovascular) disease. As components of macrophage CD40-signaling have the potential to be amenable to pharmacological manipulation, we will establish their feasibility as novel targets for (CVD) treatment.
Summary
Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVD), is a lipid driven, inflammatory disease of the large arteries. Despite a 25% relative risk reduction achieved by lipid-lowering treatment, the vast majority of atherosclerosis-induced CVD risk remains unaddressed. Therefore, characterizing mediators of the inflammatory aspect of atherosclerosis is a widely recognized scientific goal with great therapeutic implications.
Co-stimulatory molecules are key players in modulating immune interactions. My laboratory has defined the co-stimulatory CD40-CD40L dyad as a major driver of atherosclerosis. Inhibition of CD40, and of its interaction with the adaptor molecule TRAF6 by genetic deficiency, antibody treatment or (nanoparticle based) small molecule inhibitor (SMI) treatment, is one of the most powerful therapies to reduce atherosclerosis in a laboratory setting. Although CD40-CD40L interactions are associated with adaptive immunity, I recently identified the macrophage as a driver of CD40-induced inflammation in atherosclerosis. We will use state-of-the-art in vitro experiments, live cell-, super resolution imaging, proteomics approaches and mutant mouse models to unravel the role of macrophage CD40 in atherosclerosis. Moreover, using structure based virtual ligand screening, I will develop lead SMIs targeting macrophage CD40-signaling, which I will deliver using macrophage-targeting nanoparticles. My goal is to define the role of macrophage CD40 in inflammation and immunity and disentangle how its activation affects atherosclerosis. I will finally test the feasibility of targeting macrophage CD40-signaling as a treatment for CVD.
These studies will define the role of CD40-signaling in the innate immune system in health and (cardiovascular) disease. As components of macrophage CD40-signaling have the potential to be amenable to pharmacological manipulation, we will establish their feasibility as novel targets for (CVD) treatment.
Max ERC Funding
1 999 420 €
Duration
Start date: 2016-12-01, End date: 2021-11-30
Project acronym DigitalDoctors
Project Making Clinical Sense: A comparative study of how doctors learn in digital times
Researcher (PI) Anna Harris
Host Institution (HI) UNIVERSITEIT MAASTRICHT
Call Details Starting Grant (StG), SH3, ERC-2015-STG
Summary Digital technologies are reconfiguring medical practices in ways we still don’t understand. This research project seeks to examine the impact of the digital in medicine by studying the role of pedagogical technologies in how doctors learn the skills of their profession. It focuses on the centuries-old skill of physical examination; a sensing of the body, through the body. Increasingly medical students are learning these skills away from the bedside, through videos, simulated models and in laboratories. My research team will interrogate how learning with these technologies impacts on how doctors learn to sense bodies. Through the rich case of doctors-in-training the study addresses a key challenge in social scientific scholarship regarding how technologies, particularly those digital and virtual, are implicated in bodily, sensory knowing of the world. Our research takes a historically-attuned comparative anthropology approach, advancing the social study of medicine and medical education research in three new directions. First, a team of three ethnographers will attend to both spectacular and mundane technologies in medical education, recognising that everyday learning situations are filled with technologies old and new. Second, it offers the first comparative social study of medical education with fieldwork in three materially and culturally different settings in Western and Eastern Europe, and West Africa. Finally, the study brings historical and ethnographic research of technologies closer together, with a historian conducting oral histories and archival research at each site. Findings will have impact in the social sciences and education research by advancing understanding of how the digital and other technologies are implicated in skills learning. The study will develop novel digital-sensory methodologies and boldly, a new theory of techno-perception. These academic contributions will have practical relevance by improving the training of doctors in digital times.
Summary
Digital technologies are reconfiguring medical practices in ways we still don’t understand. This research project seeks to examine the impact of the digital in medicine by studying the role of pedagogical technologies in how doctors learn the skills of their profession. It focuses on the centuries-old skill of physical examination; a sensing of the body, through the body. Increasingly medical students are learning these skills away from the bedside, through videos, simulated models and in laboratories. My research team will interrogate how learning with these technologies impacts on how doctors learn to sense bodies. Through the rich case of doctors-in-training the study addresses a key challenge in social scientific scholarship regarding how technologies, particularly those digital and virtual, are implicated in bodily, sensory knowing of the world. Our research takes a historically-attuned comparative anthropology approach, advancing the social study of medicine and medical education research in three new directions. First, a team of three ethnographers will attend to both spectacular and mundane technologies in medical education, recognising that everyday learning situations are filled with technologies old and new. Second, it offers the first comparative social study of medical education with fieldwork in three materially and culturally different settings in Western and Eastern Europe, and West Africa. Finally, the study brings historical and ethnographic research of technologies closer together, with a historian conducting oral histories and archival research at each site. Findings will have impact in the social sciences and education research by advancing understanding of how the digital and other technologies are implicated in skills learning. The study will develop novel digital-sensory methodologies and boldly, a new theory of techno-perception. These academic contributions will have practical relevance by improving the training of doctors in digital times.
Max ERC Funding
1 361 507 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym MO-TRAYL
Project Mobility trajectories of young lives: Life chances of transnational youths in Global South and North
Researcher (PI) Valentina Mazzucato
Host Institution (HI) UNIVERSITEIT MAASTRICHT
Call Details Consolidator Grant (CoG), SH3, ERC-2015-CoG
Summary The objective of MO-TRAYL is to develop a better understanding of the relationship between migration and young people’s life-chances by studying youth’s mobility trajectories. How the life chances of youths, defined as their educational performance, psychological well-being and transitions into adulthood, are impacted by migration are of relevance for European cities that are faced with a growing youth population with migrant background. At the same time, cities in the Global South, where many migrants in Europe originate from, are faced with large portions of the population of minors who are living without at least one of their parents due to their parent’s migration. There is growing concern in both academia and policy about how these ‘stay-behind’ children are faring. Yet little is known about how migration impacts young people in the Global North and South in the medium-term, in part because our conception of young people’s mobility patterns has to date been overly simplified (either they move once, or they do not). This results in a lack of data that specifically looks at the different mobility patterns of young people and hardly any that has a longitudinal dimension. MO-TRAYL will break new ground by studying simultaneously youths in the Global South who have remained ‘at home’ and those who have migrated to Europe by making use of unique new longitudinal data collected in the Global South as well as collecting new data in the Global North that specifically traces the mobility trajectories, the resulting different family compositions along the way, and how both affect life chances. Through a transnational perspective in which family members and events spanning home and host countries are brought to bear on life chances, MO-TRAYL aims to re-conceptualize youth mobility and families and add a longitudinal dimension to the study of migration and life chance outcomes. The project focuses on Ghanaian children in Ghana, The Netherlands, Belgium and Germany.
Summary
The objective of MO-TRAYL is to develop a better understanding of the relationship between migration and young people’s life-chances by studying youth’s mobility trajectories. How the life chances of youths, defined as their educational performance, psychological well-being and transitions into adulthood, are impacted by migration are of relevance for European cities that are faced with a growing youth population with migrant background. At the same time, cities in the Global South, where many migrants in Europe originate from, are faced with large portions of the population of minors who are living without at least one of their parents due to their parent’s migration. There is growing concern in both academia and policy about how these ‘stay-behind’ children are faring. Yet little is known about how migration impacts young people in the Global North and South in the medium-term, in part because our conception of young people’s mobility patterns has to date been overly simplified (either they move once, or they do not). This results in a lack of data that specifically looks at the different mobility patterns of young people and hardly any that has a longitudinal dimension. MO-TRAYL will break new ground by studying simultaneously youths in the Global South who have remained ‘at home’ and those who have migrated to Europe by making use of unique new longitudinal data collected in the Global South as well as collecting new data in the Global North that specifically traces the mobility trajectories, the resulting different family compositions along the way, and how both affect life chances. Through a transnational perspective in which family members and events spanning home and host countries are brought to bear on life chances, MO-TRAYL aims to re-conceptualize youth mobility and families and add a longitudinal dimension to the study of migration and life chance outcomes. The project focuses on Ghanaian children in Ghana, The Netherlands, Belgium and Germany.
Max ERC Funding
1 937 500 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym TENSION
Project Targeting replication stress recovery pathways in oncology
Researcher (PI) Marcel van vugt
Host Institution (HI) ACADEMISCH ZIEKENHUIS GRONINGEN
Call Details Consolidator Grant (CoG), LS4, ERC-2015-CoG
Summary Genomic instability characterizes tumors, which have no clear ‘oncogenic-driver’ mutation, including triple-negative breast cancers (TNBCs). These patients do not benefit from molecularly targeted treatment and urgently need better treatment options. Increasing evidence points to replication stress as the driver of genomic instability. Since replication stress compromises cell viability, cells have evolved mechanisms to mitigate this threat.
Recently, I discovered a novel cellular mechanism—mitotic Replication Stress Recovery (RSR)—that acts as an ‘emergency brake’ during mitosis, allowing recovery from high levels of replication stress. This machinery is critical for tumor cell survival, and therefore constitutes a promising target for anti-cancer drug development. However, it is unclear how this mitotic RSR is organized molecularly and how it can be targeted therapeutically.
In this project, I aim to molecularly define and therapeutically target the Mitotic Replication Stress Recovery (RSR) machinery in triple-negative breast cancer cells.
To this end, I will implement a series of complementary innovative strategies. First, I will use mass-spec-based proteomics to molecularly characterize components and wiring of the mitotic RSR machinery. Second, to identify the genetic profiles of cancer subgroups that are sensitive to inactivation of the mitotic RSR, functional genetic screens will be combined with visualization and quantification of replication stress in genomically-defined human cancer samples. Finally, my findings will be translated to the pre-clinical situation by exploring the feasibility of therapeutic inactivation of the RSR machinery in vitro and in vivo in a panel of triple-negative breast cancer models.
In summary, TENSION will provide advanced insight into the composition and wiring of the mitotic RSR machinery and will reveal the potency of targeting this pathway therapeutically for TNBCs and other hard-to-treat, genomically instable cancers.
Summary
Genomic instability characterizes tumors, which have no clear ‘oncogenic-driver’ mutation, including triple-negative breast cancers (TNBCs). These patients do not benefit from molecularly targeted treatment and urgently need better treatment options. Increasing evidence points to replication stress as the driver of genomic instability. Since replication stress compromises cell viability, cells have evolved mechanisms to mitigate this threat.
Recently, I discovered a novel cellular mechanism—mitotic Replication Stress Recovery (RSR)—that acts as an ‘emergency brake’ during mitosis, allowing recovery from high levels of replication stress. This machinery is critical for tumor cell survival, and therefore constitutes a promising target for anti-cancer drug development. However, it is unclear how this mitotic RSR is organized molecularly and how it can be targeted therapeutically.
In this project, I aim to molecularly define and therapeutically target the Mitotic Replication Stress Recovery (RSR) machinery in triple-negative breast cancer cells.
To this end, I will implement a series of complementary innovative strategies. First, I will use mass-spec-based proteomics to molecularly characterize components and wiring of the mitotic RSR machinery. Second, to identify the genetic profiles of cancer subgroups that are sensitive to inactivation of the mitotic RSR, functional genetic screens will be combined with visualization and quantification of replication stress in genomically-defined human cancer samples. Finally, my findings will be translated to the pre-clinical situation by exploring the feasibility of therapeutic inactivation of the RSR machinery in vitro and in vivo in a panel of triple-negative breast cancer models.
In summary, TENSION will provide advanced insight into the composition and wiring of the mitotic RSR machinery and will reveal the potency of targeting this pathway therapeutically for TNBCs and other hard-to-treat, genomically instable cancers.
Max ERC Funding
1 972 500 €
Duration
Start date: 2016-08-01, End date: 2021-07-31
Project acronym TSGPs-of-CFSs
Project Role of Tumour Suppressor Gene Products of Common Fragile Sites in Human Diseases
Researcher (PI) Rami Aqeilan
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Consolidator Grant (CoG), LS4, ERC-2015-CoG
Summary Common fragile sites (CFSs) are large chromosomal regions identified by conventional cytogenetics as sequences prone to breakage in cells subjected to replication stress. The interest in CFSs stems from their key role in DNA damage, resulting in chromosomal rearrangements. The instability of CFSs was correlated with genome instability in precancerous lesions and during tumour progression. Two opposing views dominate the discussion regarding the role of CFSs. One school of thought suggested that genomic instability during cancer progression causes collateral damage to genes residing within CFSs, such as WWOX and FHIT. These genes are proposed to be unselected ‘‘passenger’’ mutations. The counter argument is that deletions and other genomic alterations in CFSs occur early in cancer development. Cancer cells with deletions in genes that span CFSs are then selectively expanded due to loss of tumour suppressor functions such as protection of genome stability, coordination of cell cycle or apoptosis.
Recent observations from my lab clearly suggest that gene products from CFSs play driver roles in cancer transformation. Moreover, we have evidence for the involvement of DNA damage and Wwox in pancreatic β-cells in the context of diabetes. Here, I propose to investigate the role of tumour suppressor gene products (TSGPs) of CFSs in human diseases. Three approaches will be taken to tackle this question. First, molecular functions of TSGPs of CFSs will be determined using state-of-the-art genetic tools in vitro. Second, novel transgenic mouse tools will be used to study CFSs and their associated TSGs in preneoplastic lesions and tumours in vivo, with confirmatory studies in human material. Third, we will examine the potential involvement of CFSs and their TSGPs in type-2 diabetes (T2D).
The expected outcome is a detailed molecular understanding of CFSs and their associated TSGPs in genomic instability as well as their roles in cancer and metabolic diseases.
Summary
Common fragile sites (CFSs) are large chromosomal regions identified by conventional cytogenetics as sequences prone to breakage in cells subjected to replication stress. The interest in CFSs stems from their key role in DNA damage, resulting in chromosomal rearrangements. The instability of CFSs was correlated with genome instability in precancerous lesions and during tumour progression. Two opposing views dominate the discussion regarding the role of CFSs. One school of thought suggested that genomic instability during cancer progression causes collateral damage to genes residing within CFSs, such as WWOX and FHIT. These genes are proposed to be unselected ‘‘passenger’’ mutations. The counter argument is that deletions and other genomic alterations in CFSs occur early in cancer development. Cancer cells with deletions in genes that span CFSs are then selectively expanded due to loss of tumour suppressor functions such as protection of genome stability, coordination of cell cycle or apoptosis.
Recent observations from my lab clearly suggest that gene products from CFSs play driver roles in cancer transformation. Moreover, we have evidence for the involvement of DNA damage and Wwox in pancreatic β-cells in the context of diabetes. Here, I propose to investigate the role of tumour suppressor gene products (TSGPs) of CFSs in human diseases. Three approaches will be taken to tackle this question. First, molecular functions of TSGPs of CFSs will be determined using state-of-the-art genetic tools in vitro. Second, novel transgenic mouse tools will be used to study CFSs and their associated TSGs in preneoplastic lesions and tumours in vivo, with confirmatory studies in human material. Third, we will examine the potential involvement of CFSs and their TSGPs in type-2 diabetes (T2D).
The expected outcome is a detailed molecular understanding of CFSs and their associated TSGPs in genomic instability as well as their roles in cancer and metabolic diseases.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
Project acronym UMnD
Project Urban modelling in higher dimensions: embedding generalisation of 3D data in a 4D model
Researcher (PI) Jantine Esther Stoter
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Call Details Starting Grant (StG), SH3, ERC-2015-STG
Summary Geographic data about urban objects (buildings, roads) is needed to monitor and control processes within modern urban areas (noise, flooding, energy demand-supply). As these processes occur in 3D, urban applications require 3D data and each application requires its own specific semantic and geometric Level of Detail (LoD) of the 3D data.
The scientific challenge of this project is that it requires enormous efforts to collect and transform 3D data to make it suitable for a specific application. Urban applications are therefore forced to work mainly in 2D. This reduction causes the loss of important information. A solution is needed to support the reuse of once collected 3D data in multiple applications.
I will develop a fundamental solution for providing 3D data at application specific LoDs to solve the current problem of independently acquired and stored LoDs of a 3D urban model. To enforce consistency across dimensions, the LoDs will be modelled as an extra dimension to the 3D spatial dimensions in an integrated 3D+LoD (4D) model. I will use an innovative method that goes far beyond the state-of-the-art by introducing higher dimensional (nD) mathematical models to the well-established domain of cartographic generalisation in 2D. Furthermore, I will study 3D generalisation solutions to derive coarse from fine data and embed these in the 4D model. “Slicing” operations will be developed that reduce the dimensions of the 4D data to generate error-free 3D data at application specific LoDs.
LoD is strongly related to map scale, a well-known concept in GIS. However, modelling it as an extra dimension of geographic data is new. In addition, the intermediate results have the potential to advance the field of geo-information technology, such as the ground-breaking extension of the 2D cartographic generalisation domain to 3D. If successful, the 4D approach opens a new horizon for modelling parametrisable aspects of urban environments, which may establish a new research line.
Summary
Geographic data about urban objects (buildings, roads) is needed to monitor and control processes within modern urban areas (noise, flooding, energy demand-supply). As these processes occur in 3D, urban applications require 3D data and each application requires its own specific semantic and geometric Level of Detail (LoD) of the 3D data.
The scientific challenge of this project is that it requires enormous efforts to collect and transform 3D data to make it suitable for a specific application. Urban applications are therefore forced to work mainly in 2D. This reduction causes the loss of important information. A solution is needed to support the reuse of once collected 3D data in multiple applications.
I will develop a fundamental solution for providing 3D data at application specific LoDs to solve the current problem of independently acquired and stored LoDs of a 3D urban model. To enforce consistency across dimensions, the LoDs will be modelled as an extra dimension to the 3D spatial dimensions in an integrated 3D+LoD (4D) model. I will use an innovative method that goes far beyond the state-of-the-art by introducing higher dimensional (nD) mathematical models to the well-established domain of cartographic generalisation in 2D. Furthermore, I will study 3D generalisation solutions to derive coarse from fine data and embed these in the 4D model. “Slicing” operations will be developed that reduce the dimensions of the 4D data to generate error-free 3D data at application specific LoDs.
LoD is strongly related to map scale, a well-known concept in GIS. However, modelling it as an extra dimension of geographic data is new. In addition, the intermediate results have the potential to advance the field of geo-information technology, such as the ground-breaking extension of the 2D cartographic generalisation domain to 3D. If successful, the 4D approach opens a new horizon for modelling parametrisable aspects of urban environments, which may establish a new research line.
Max ERC Funding
1 498 148 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
