Project acronym PHYRIST
Project Physiological roles of the Ribotoxic Stress Response
Researcher (PI) Simon Holst BEKKER-JENSEN
Host Institution (HI) KOBENHAVNS UNIVERSITET
Country Denmark
Call Details Consolidator Grant (CoG), LS4, ERC-2019-COG
Summary The ribotoxic stress response (RSR) surveys the structural and functional integrity of ribosomes and is triggered by diverse groups of ribotoxins (e.g. ricin), UV irradiation and some chemotherapeutics. When presented with impaired ribosomes, the proximal MAPKKK ZAK activates MAP kinases p38 and JNK to initiate a powerful inflammatory response. This signalling contributes to the detrimental reactions to ribotoxins and fatal side effects of cancer therapy. However, despite decades of research into the RSR, the physiological relevance of the underlying pathway in whole organisms is unknown. I hypothesize that the RSR constitutes a general translation quality control pathway and hence I aim to uncover the physiological and pathological implications of RSR impairment in mice and nematodes.
In one line of investigation, I will elucidate the connections between UV radiation and RSR-mediated p38 activation. I hypothesize that this signalling pathway is critical for sunlight-induced skin inflammation and development of skin cancers of different cellular origins. Rewardingly, we found that cells from our ZAK knockout (KO) mice are refractory to UV-induced p38 activation, which is a significant contributor to skin cancer development. My team has also observed deregulation of protein translation in RSR-deficient human and mouse cells, and a reduced lifespan of ZAK KO nematodes. Thus encouraged, I will determine the impact of the RSR pathway on cancer development and aging processes in mice, and I will unravel the molecular connections between defective ribosomes, RSR activation and regulation of translation. Finally, I am in a unique position to evaluate the RSR as a putative drug target and I will investigate the potential of ZAK inhibition to treat or prevent skin cancer, and to remedy inflammation arising from infection with ribotoxin-producing bacteria. In sum, PHYRIST will yield the first detailed insight into the in vivo relevance of the ribotoxic stress response.
Summary
The ribotoxic stress response (RSR) surveys the structural and functional integrity of ribosomes and is triggered by diverse groups of ribotoxins (e.g. ricin), UV irradiation and some chemotherapeutics. When presented with impaired ribosomes, the proximal MAPKKK ZAK activates MAP kinases p38 and JNK to initiate a powerful inflammatory response. This signalling contributes to the detrimental reactions to ribotoxins and fatal side effects of cancer therapy. However, despite decades of research into the RSR, the physiological relevance of the underlying pathway in whole organisms is unknown. I hypothesize that the RSR constitutes a general translation quality control pathway and hence I aim to uncover the physiological and pathological implications of RSR impairment in mice and nematodes.
In one line of investigation, I will elucidate the connections between UV radiation and RSR-mediated p38 activation. I hypothesize that this signalling pathway is critical for sunlight-induced skin inflammation and development of skin cancers of different cellular origins. Rewardingly, we found that cells from our ZAK knockout (KO) mice are refractory to UV-induced p38 activation, which is a significant contributor to skin cancer development. My team has also observed deregulation of protein translation in RSR-deficient human and mouse cells, and a reduced lifespan of ZAK KO nematodes. Thus encouraged, I will determine the impact of the RSR pathway on cancer development and aging processes in mice, and I will unravel the molecular connections between defective ribosomes, RSR activation and regulation of translation. Finally, I am in a unique position to evaluate the RSR as a putative drug target and I will investigate the potential of ZAK inhibition to treat or prevent skin cancer, and to remedy inflammation arising from infection with ribotoxin-producing bacteria. In sum, PHYRIST will yield the first detailed insight into the in vivo relevance of the ribotoxic stress response.
Max ERC Funding
1 997 678 €
Duration
Start date: 2020-06-01, End date: 2025-05-31
Project acronym PLEDGEDEM
Project Pledges in democracy
Researcher (PI) Carsten JENSEN
Host Institution (HI) AARHUS UNIVERSITET
Country Denmark
Call Details Consolidator Grant (CoG), SH2, ERC-2018-COG
Summary Election pledges are supposedly a vital part of representative democracy. Yet we do not in fact know whether and how pledges matter for vote choice and accountability. This project thus asks: Do election pledges matter for voters’ democratic behavior and beliefs?
The role of pledges in citizens’ democratic behavior and beliefs is, surprisingly, virtually unexplored. This project’s ambition is therefore to create a new research agenda that redefines how political scientists think about the link between parties and voters. The project not only advances the research frontier by introducing a new, crucial phenomenon for political scientists to study; it also breaks new ground because it provides original theoretical and methodological tools for this new research agenda.
The key empirical contribution of this project is to collect two path-breaking datasets in the United States, France, and Norway that produce an unbiased estimate of voters’ awareness and use of pledges. The first consists of a set of innovative panel surveys with embedded conjoint experiments conducted both before and after national elections. The second dataset codes all pledges; whether or not they are broken; and how the mass media report on them.
This project is unique in its scientific ambition: It studies the core mechanism of representative democracy as it happens in real time, and does so in several countries. If successful, we will have much firmer knowledge about how voters select parties that best represent them and sanction those that betray their trust – and what this all implies for people’s trust in democracy.
Summary
Election pledges are supposedly a vital part of representative democracy. Yet we do not in fact know whether and how pledges matter for vote choice and accountability. This project thus asks: Do election pledges matter for voters’ democratic behavior and beliefs?
The role of pledges in citizens’ democratic behavior and beliefs is, surprisingly, virtually unexplored. This project’s ambition is therefore to create a new research agenda that redefines how political scientists think about the link between parties and voters. The project not only advances the research frontier by introducing a new, crucial phenomenon for political scientists to study; it also breaks new ground because it provides original theoretical and methodological tools for this new research agenda.
The key empirical contribution of this project is to collect two path-breaking datasets in the United States, France, and Norway that produce an unbiased estimate of voters’ awareness and use of pledges. The first consists of a set of innovative panel surveys with embedded conjoint experiments conducted both before and after national elections. The second dataset codes all pledges; whether or not they are broken; and how the mass media report on them.
This project is unique in its scientific ambition: It studies the core mechanism of representative democracy as it happens in real time, and does so in several countries. If successful, we will have much firmer knowledge about how voters select parties that best represent them and sanction those that betray their trust – and what this all implies for people’s trust in democracy.
Max ERC Funding
1 999 255 €
Duration
Start date: 2019-08-01, End date: 2025-01-31
Project acronym StemHealth
Project Foetal Intestinal Stem Cells in Biology and Health
Researcher (PI) Kim Bak Jensen
Host Institution (HI) KOBENHAVNS UNIVERSITET
Country Denmark
Call Details Consolidator Grant (CoG), LS7, ERC-2015-CoG
Summary There is currently no medical cure for the millions of individuals affected by inflammatory bowel disease (IBD). These patients suffer from bleeding along the gastrointestinal tract due to epithelial ulceration, which causes severe abdominal pain, diarrhoea and malnutrition. This is due to the severely compromised integrity of the intestinal epithelium. I propose that patients with IBD will benefit from an intestinal epithelial transplant.
The objectives of this research programme are two fold. Firstly, I propose to perform preclinical testing of human intestinal epithelium to pave the way for their inclusion in clinical trials for IBD patients. This will be based on a combination of state-of-the-art cell culture methods with novel transplantation methodology. By combining analysis of intestinal epithelial cells from various developmental stages, I will be able to identify the most suitable source for transplantation and define how adult stem cells are specified in the tissue. Secondly, I will utilise an in vitro culture system to identify the transcriptional networks responsible for the maturation of the foetal intestinal epithelium. Tissue maturation currently constitutes a major roadblock in regenerative medicine as cells derived from foetal and pluripotent stem cells have foetal properties. Understanding this process will therefore improve our ability to generate sustainable sources of cells for transplantation, which is pivotal for future therapies relying on regenerative medicine and in vitro modelling of disease
The proposed research programme will have significant clinical and biological impact. Clinically, it provides the framework for initiating clinical trials for patients with IBD and protocols to obtain mature adult epithelium for in vitro disease modelling. From a biological perspective, we will gain insights into how specific signalling networks maintain specific cell states and dictate tissue maturation.
Summary
There is currently no medical cure for the millions of individuals affected by inflammatory bowel disease (IBD). These patients suffer from bleeding along the gastrointestinal tract due to epithelial ulceration, which causes severe abdominal pain, diarrhoea and malnutrition. This is due to the severely compromised integrity of the intestinal epithelium. I propose that patients with IBD will benefit from an intestinal epithelial transplant.
The objectives of this research programme are two fold. Firstly, I propose to perform preclinical testing of human intestinal epithelium to pave the way for their inclusion in clinical trials for IBD patients. This will be based on a combination of state-of-the-art cell culture methods with novel transplantation methodology. By combining analysis of intestinal epithelial cells from various developmental stages, I will be able to identify the most suitable source for transplantation and define how adult stem cells are specified in the tissue. Secondly, I will utilise an in vitro culture system to identify the transcriptional networks responsible for the maturation of the foetal intestinal epithelium. Tissue maturation currently constitutes a major roadblock in regenerative medicine as cells derived from foetal and pluripotent stem cells have foetal properties. Understanding this process will therefore improve our ability to generate sustainable sources of cells for transplantation, which is pivotal for future therapies relying on regenerative medicine and in vitro modelling of disease
The proposed research programme will have significant clinical and biological impact. Clinically, it provides the framework for initiating clinical trials for patients with IBD and protocols to obtain mature adult epithelium for in vitro disease modelling. From a biological perspective, we will gain insights into how specific signalling networks maintain specific cell states and dictate tissue maturation.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-08-01, End date: 2022-07-31
