Project acronym BBBARRIER
Project Mechanisms of regulation of the blood-brain barrier; towards opening and closing the barrier on demand
Researcher (PI) Bjoern Christer Betsholtz
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), LS4, ERC-2011-ADG_20110310
Summary In the bone-enclosed CNS, increased vascular permeability may cause life-threatening tissue swelling, and/or ischemia and inflammation which compromise tissue repair after trauma or stroke. The brain vasculature possesses several unique features collectively named the blood-brain barrier (BBB) in which passive permeability is almost completely abolished and replaced by a complex of specific transport mechanisms. The BBB is necessary to uphold the specific milieu necessary for neuronal function. Whereas breakdown of the BBB is part of many CNS diseases, including stroke, neuroinflammation, trauma and neurodegenerative disorders, its molecular mechanisms and consequences are unclear and debated. Conversely, the intact BBB is a huge obstacle for drug delivery to the brain. Research on the BBB therefore has two seemingly opposing aims: 1) to seal a damaged BBB and protect the brain from toxic blood products, and 2) to open the BBB “on demand” for drug delivery. A major problem in the BBB field has been the lack of in vivo animal models for molecular and functional studies. So far, available in vitro models are not recapitulating the in vivo BBB. Our recent work on mouse models lacking pericytes, a BBB-associated cell type, demonstrates a specific role for pericytes in the development and regulation of the mammalian BBB. These animal models are the first ones showing a general and significant BBB impairment in adulthood, and as such they provide a unique opportunity to address molecular mechanisms of BBB disruption in disease and in drug transport across the BBB. Importantly, the new models and tools that we have developed allow us to search for relevant druggable mechanisms and molecular targets in the BBB. The long-term goals of this proposal are to develop molecular strategies and tools to open and close the BBB “on demand” for drug delivery to the CNS, and to explore the importance and mechanisms of BBB dysfunction in neurodegenerative diseases and stroke.
Summary
In the bone-enclosed CNS, increased vascular permeability may cause life-threatening tissue swelling, and/or ischemia and inflammation which compromise tissue repair after trauma or stroke. The brain vasculature possesses several unique features collectively named the blood-brain barrier (BBB) in which passive permeability is almost completely abolished and replaced by a complex of specific transport mechanisms. The BBB is necessary to uphold the specific milieu necessary for neuronal function. Whereas breakdown of the BBB is part of many CNS diseases, including stroke, neuroinflammation, trauma and neurodegenerative disorders, its molecular mechanisms and consequences are unclear and debated. Conversely, the intact BBB is a huge obstacle for drug delivery to the brain. Research on the BBB therefore has two seemingly opposing aims: 1) to seal a damaged BBB and protect the brain from toxic blood products, and 2) to open the BBB “on demand” for drug delivery. A major problem in the BBB field has been the lack of in vivo animal models for molecular and functional studies. So far, available in vitro models are not recapitulating the in vivo BBB. Our recent work on mouse models lacking pericytes, a BBB-associated cell type, demonstrates a specific role for pericytes in the development and regulation of the mammalian BBB. These animal models are the first ones showing a general and significant BBB impairment in adulthood, and as such they provide a unique opportunity to address molecular mechanisms of BBB disruption in disease and in drug transport across the BBB. Importantly, the new models and tools that we have developed allow us to search for relevant druggable mechanisms and molecular targets in the BBB. The long-term goals of this proposal are to develop molecular strategies and tools to open and close the BBB “on demand” for drug delivery to the CNS, and to explore the importance and mechanisms of BBB dysfunction in neurodegenerative diseases and stroke.
Max ERC Funding
2 499 427 €
Duration
Start date: 2012-08-01, End date: 2017-07-31
Project acronym mtDNA-CURE
Project Treating mitochondrial disease caused by pathogenic mtDNA mutations
Researcher (PI) Nils-Goeran LARSSON
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Advanced Grant (AdG), LS4, ERC-2016-ADG
Summary This proposal describes a series of powerful experimental strategies to develop a completely novel treatment for mtDNA mutation disease based on identifying unknown mechanisms controlling mtDNA replication. Several hundred different mtDNA mutations affect tRNA genes and impair mitochondrial translation leading to human disease. There is typically heteroplasmy with a mixture of wild-type and mutated mtDNA, and the mutations are acting in a “recessive” (loss of function) way. Very high levels of mutated mtDNA are needed to cause disease in affected patients whereas maternal relatives with high, but sub-threshold levels of mutated mtDNA are completely healthy. The corollary of these observations is that even a small increase of wild-type mtDNA may efficiently counteract disease in affected patients. This hypothesis will be validated by a series of genetic experiments with mice harbouring single pathogenic mtDNA mutations. Furthermore, novel factors controlling mtDNA replication will be identified. In particular, we will elucidate the formation and function of the mammalian displacement (D) loop, which provides a switch between abortive and genome length mtDNA replication. This very fundamental problem in mammalian mitochondrial biology has remained unsolved for decades, but I feel that the innovative experimental strategies I present in this proposal are very powerful and should have a fair chance of being successful. In any circumstance, the project will provide important molecular insights into novel mechanisms relevant for mammalian mtDNA replication. Over the years I have been strongly convinced that congruent results from in vivo and in vitro studies are needed to obtain reliable mechanistic insights and this project is therefore based on the close integration of biochemistry, advanced proteomics and state-of-the-art mouse and fly genetics. Finally, I describe a powerful large-scale screening approach to develop small molecular stimulators of mtDNA replication.
Summary
This proposal describes a series of powerful experimental strategies to develop a completely novel treatment for mtDNA mutation disease based on identifying unknown mechanisms controlling mtDNA replication. Several hundred different mtDNA mutations affect tRNA genes and impair mitochondrial translation leading to human disease. There is typically heteroplasmy with a mixture of wild-type and mutated mtDNA, and the mutations are acting in a “recessive” (loss of function) way. Very high levels of mutated mtDNA are needed to cause disease in affected patients whereas maternal relatives with high, but sub-threshold levels of mutated mtDNA are completely healthy. The corollary of these observations is that even a small increase of wild-type mtDNA may efficiently counteract disease in affected patients. This hypothesis will be validated by a series of genetic experiments with mice harbouring single pathogenic mtDNA mutations. Furthermore, novel factors controlling mtDNA replication will be identified. In particular, we will elucidate the formation and function of the mammalian displacement (D) loop, which provides a switch between abortive and genome length mtDNA replication. This very fundamental problem in mammalian mitochondrial biology has remained unsolved for decades, but I feel that the innovative experimental strategies I present in this proposal are very powerful and should have a fair chance of being successful. In any circumstance, the project will provide important molecular insights into novel mechanisms relevant for mammalian mtDNA replication. Over the years I have been strongly convinced that congruent results from in vivo and in vitro studies are needed to obtain reliable mechanistic insights and this project is therefore based on the close integration of biochemistry, advanced proteomics and state-of-the-art mouse and fly genetics. Finally, I describe a powerful large-scale screening approach to develop small molecular stimulators of mtDNA replication.
Max ERC Funding
2 500 000 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym SET-NET
Project Enzymatic and genomic targets of histone modifying enzymes and their role in liver metabolism and hepatocarcinogenesis
Researcher (PI) Ioannis Talianidis
Host Institution (HI) BIOMEDICAL SCIENCES RESEARCH CENTER ALEXANDER FLEMING
Country Greece
Call Details Advanced Grant (AdG), LS4, ERC-2011-ADG_20110310
Summary "In this proposal we will study the role of histone methytransferases Set9, PR-SET7, Smyd2, Smyd3 and the demethylase LSD1 in hepatocarcinogenesis and in the regulation of hepatic metabolic pathways.
The hypothesis raised here suggests that the function of histone modifying enzymes is realized through 4 overlapping regulatory layers: i. via modifications of chromatin, ii. via modifications of recently identified transcription factor substrates, iii. via influencing the hepatic transcription factor crossregulatory circuitry, and iv. via modification of each other.
To dissect the role of these regulatory layers and determine their contribution in the control of hepatic metabolic pathways, and in the development of hepatocellular carcinoma, our activities will involve: i. Generation of relevant KO and transgenic mouse models, ii. Functional characterization of novel non-histone and histone substrates, iii. Analysis of novel cross-regulatory protein modifications affecting the activity of the enzymes and iv. the identification of their genomic targets and associated chromatin modifications using global approaches.
The work is expected to provide important insights into a previously unanticipated network of protein methylation-directed regulatory modules, potentially operating in multiple biological pathways such as liver development, metabolism, apoptosis and carcinogenesis. The functioning of such network would be of high biological importance, with far-reaching implications in drug development, rivaling those of phosphorylation or acetylation regulated processes."
Summary
"In this proposal we will study the role of histone methytransferases Set9, PR-SET7, Smyd2, Smyd3 and the demethylase LSD1 in hepatocarcinogenesis and in the regulation of hepatic metabolic pathways.
The hypothesis raised here suggests that the function of histone modifying enzymes is realized through 4 overlapping regulatory layers: i. via modifications of chromatin, ii. via modifications of recently identified transcription factor substrates, iii. via influencing the hepatic transcription factor crossregulatory circuitry, and iv. via modification of each other.
To dissect the role of these regulatory layers and determine their contribution in the control of hepatic metabolic pathways, and in the development of hepatocellular carcinoma, our activities will involve: i. Generation of relevant KO and transgenic mouse models, ii. Functional characterization of novel non-histone and histone substrates, iii. Analysis of novel cross-regulatory protein modifications affecting the activity of the enzymes and iv. the identification of their genomic targets and associated chromatin modifications using global approaches.
The work is expected to provide important insights into a previously unanticipated network of protein methylation-directed regulatory modules, potentially operating in multiple biological pathways such as liver development, metabolism, apoptosis and carcinogenesis. The functioning of such network would be of high biological importance, with far-reaching implications in drug development, rivaling those of phosphorylation or acetylation regulated processes."
Max ERC Funding
2 499 600 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
