Project acronym CASINO
Project Carbohydrate signals controlling nodulation
Researcher (PI) Jens Stougaard Jensen
Host Institution (HI) AARHUS UNIVERSITET
Country Denmark
Call Details Advanced Grant (AdG), LS3, ERC-2010-AdG_20100317
Summary Mechanisms governing interaction between multicellular organisms and microbes are central for understanding pathogenesis, symbiosis and the function of ecosystems. We propose to address these mechanisms by pioneering an interdisciplinary approach for understanding cellular signalling, response processes and organ development. The challenge is to determine factors synchronising three processes, organogenesis, infection thread formation and bacterial infection, running in parallel to build a root nodule hosting symbiotic bacteria. We aim to exploit the unique possibilities for analysing endocytosis of bacteria in model legumes and to develop genomic, genetic and biological chemistry tools to break new ground in our understanding of carbohydrates in plant development and plant-microbe interaction. Surface exposed rhizobial polysaccharides play a crucial but poorly understood role in infection thread formation and rhizobial invasion resulting in endocytosis. We will undertake an integrated functional characterisation of receptor-ligand mechanisms mediating recognition of secreted polysaccharides and subsequent signal amplification. So far progress in this field has been limited by the complex nature of carbohydrate polymers, lack of a suitable experimental model system where both partners in an interaction could be manipulated and lack of corresponding methods for carbohydrate synthesis, analysis and interaction studies. In this context our legume model system and the discovery that the legume Nod-factor receptors recognise bacterial lipochitin-oligosaccharide signals at their LysM domains provides a new opportunity. Combined with advanced bioorganic chemistry and nanobioscience approaches this proposal will engage the above mentioned limitations.
Summary
Mechanisms governing interaction between multicellular organisms and microbes are central for understanding pathogenesis, symbiosis and the function of ecosystems. We propose to address these mechanisms by pioneering an interdisciplinary approach for understanding cellular signalling, response processes and organ development. The challenge is to determine factors synchronising three processes, organogenesis, infection thread formation and bacterial infection, running in parallel to build a root nodule hosting symbiotic bacteria. We aim to exploit the unique possibilities for analysing endocytosis of bacteria in model legumes and to develop genomic, genetic and biological chemistry tools to break new ground in our understanding of carbohydrates in plant development and plant-microbe interaction. Surface exposed rhizobial polysaccharides play a crucial but poorly understood role in infection thread formation and rhizobial invasion resulting in endocytosis. We will undertake an integrated functional characterisation of receptor-ligand mechanisms mediating recognition of secreted polysaccharides and subsequent signal amplification. So far progress in this field has been limited by the complex nature of carbohydrate polymers, lack of a suitable experimental model system where both partners in an interaction could be manipulated and lack of corresponding methods for carbohydrate synthesis, analysis and interaction studies. In this context our legume model system and the discovery that the legume Nod-factor receptors recognise bacterial lipochitin-oligosaccharide signals at their LysM domains provides a new opportunity. Combined with advanced bioorganic chemistry and nanobioscience approaches this proposal will engage the above mentioned limitations.
Max ERC Funding
2 399 127 €
Duration
Start date: 2011-05-01, End date: 2016-04-30
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 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
Project acronym WATERUNDERTHEICE
Project Where is the water under the Greenland ice sheet?
Researcher (PI) Dorthe Dahl-Jensen
Host Institution (HI) KOBENHAVNS UNIVERSITET
Country Denmark
Call Details Advanced Grant (AdG), PE10, ERC-2009-AdG
Summary Recent analysis of radar-depth sounder data has shown that many areas of the Greenland ice sheet have melt water under the base. The extent of the wet base and distribution of melt water are poorly known. Also lakes under the ice have not been discovered in contrast with those in Antarctica. The effect of the water beneath the ice, however, is well documented: it lubricates the bed and removes the friction between the basal ice and underlying bedrock. The ice with a wet bed flows faster, reacts rapidly to changes in climate and the basal-melt water contributes to the fresh-water supply to the ocean from the Greenland ice sheet. The primary objectives of the project are to map melt water extent of the Greenland ice sheet and its impact by tracing internal layers and analyzing bedrock returns from airborne radio-echo sounding data, and use mapping results in conjunction with ice-sheet and hydrostatic models for the movement of the basal water to predict the ice-sheet s response to climate change. The information derived from deep ice-cores that reach the bed will be used to constrain models. We will also study the basal material (dust, DNA and microbiological material) and bedrock properties from the deep-ice core sites. This will add a further dimension to the study and provide opportunities to look for life under the ice and constrain the age of the Greenland ice sheet. The proposed research is a high risk project because of the difficulty in accessing basal conditions under 3-km of ice with a potential for high payoff science. The team will consist of scientists and engineers with expertise in the palaeoclimate, radar sounding and signal processing, and ice-sheet models.
Summary
Recent analysis of radar-depth sounder data has shown that many areas of the Greenland ice sheet have melt water under the base. The extent of the wet base and distribution of melt water are poorly known. Also lakes under the ice have not been discovered in contrast with those in Antarctica. The effect of the water beneath the ice, however, is well documented: it lubricates the bed and removes the friction between the basal ice and underlying bedrock. The ice with a wet bed flows faster, reacts rapidly to changes in climate and the basal-melt water contributes to the fresh-water supply to the ocean from the Greenland ice sheet. The primary objectives of the project are to map melt water extent of the Greenland ice sheet and its impact by tracing internal layers and analyzing bedrock returns from airborne radio-echo sounding data, and use mapping results in conjunction with ice-sheet and hydrostatic models for the movement of the basal water to predict the ice-sheet s response to climate change. The information derived from deep ice-cores that reach the bed will be used to constrain models. We will also study the basal material (dust, DNA and microbiological material) and bedrock properties from the deep-ice core sites. This will add a further dimension to the study and provide opportunities to look for life under the ice and constrain the age of the Greenland ice sheet. The proposed research is a high risk project because of the difficulty in accessing basal conditions under 3-km of ice with a potential for high payoff science. The team will consist of scientists and engineers with expertise in the palaeoclimate, radar sounding and signal processing, and ice-sheet models.
Max ERC Funding
2 499 999 €
Duration
Start date: 2010-01-01, End date: 2015-12-31
