Project acronym CARDIOREDOX
Project Redox sensing and signalling in cardiovascular health and disease
Researcher (PI) Philip Eaton
Host Institution (HI) KING'S COLLEGE LONDON
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary "We want to determine how oxidants are sensed and transduced into a biological effect within the cardiovascular system. The proposed work will focus on thiol-based redox sensors, defining their role in heart and blood vessel function during health and disease. Although this laboratory has studied the molecular basis of redox signaling for more than a decade, the subject is still in its relative infancy with considerable scope for major advances. Oxidant signaling remains a ‘hot topic’ with high profile studies confirming a fundamental role for redox control of protein and cellular function continuing to emerge. The molecular basis of redox sensing is the reaction of an oxidant with target proteins. This gives rise to oxidative post-translational modifications, most commonly of cysteinyl thiols, potentially altering the activity of proteins to regulate cell or tissue function. One of the reasons there are so many unanswered questions about redox sensing and signaling is the diversity of oxidant molecules produced by cells that can interact with sensor proteins to alter their function. This application is aimed at extending our knowledge of redox sensing and signalling, allowing us to define its importance in cardiovascular health and disease."
Summary
"We want to determine how oxidants are sensed and transduced into a biological effect within the cardiovascular system. The proposed work will focus on thiol-based redox sensors, defining their role in heart and blood vessel function during health and disease. Although this laboratory has studied the molecular basis of redox signaling for more than a decade, the subject is still in its relative infancy with considerable scope for major advances. Oxidant signaling remains a ‘hot topic’ with high profile studies confirming a fundamental role for redox control of protein and cellular function continuing to emerge. The molecular basis of redox sensing is the reaction of an oxidant with target proteins. This gives rise to oxidative post-translational modifications, most commonly of cysteinyl thiols, potentially altering the activity of proteins to regulate cell or tissue function. One of the reasons there are so many unanswered questions about redox sensing and signaling is the diversity of oxidant molecules produced by cells that can interact with sensor proteins to alter their function. This application is aimed at extending our knowledge of redox sensing and signalling, allowing us to define its importance in cardiovascular health and disease."
Max ERC Funding
2 255 659 €
Duration
Start date: 2013-12-01, End date: 2018-11-30
Project acronym CSI-Fun
Project Chronic Systemic Inflammation: Functional organ cross-talk in inflammatory disease and cancer
Researcher (PI) Erwin Friedrich WAGNER
Host Institution (HI) MEDIZINISCHE UNIVERSITAET WIEN
Call Details Advanced Grant (AdG), LS4, ERC-2016-ADG
Summary Chronic Systemic Inflammation (CSI) resulting from systemic release of inflammatory cytokines and activation of the immune system is responsible for the progression of several debilitating diseases, such as Psoriasis, Arthritis and Cancer. Initially localised diseases can result in CSI with subsequent systemic spread to distant organs, a key patho-physiological phase responsible for major morbidity and even mortality. Despite the importance of CSI, a complete understanding of the molecular mechanisms, signalling pathways and cell types involved, as well as the chronological evolution of the systemic inflammatory response is still elusive. The classical approach to study inflammation has focused on investigating individual cell types or organs in the pathogenesis of a single disease, thereby neglecting important organ cross-talk and systemic interactions. Furthermore, understanding the temporal and spatial kinetics modulating the inflammatory response requires a detailed study of interactions between different immune and non-immune organs at various time points during disease progression in the context of the whole organism.
The aim of this research proposal is to substantially advance our understanding of whole organ physiology in relation to systemic inflammation as a cause or/and consequence of disease with the focus on Psoriasis/Joint Diseases and Cancer Cachexia. The goal is to elucidate the molecular mechanisms at the cellular and systemic level, and to decipher endocrine interactions and cross-talks between distant organs. Various model systems ranging from cell cultures to genetically engineered mouse models to human clinical samples will be employed. Genomic, proteomic and metabolomic data will be combined with functional in vivo assessment using mouse models to understand the multi-faceted role of systemic inflammation in chronic human diseases, such as Inflammatory Skin/Joint disease and Cachexia, a deadly systemic manifestation of Cancer.
Summary
Chronic Systemic Inflammation (CSI) resulting from systemic release of inflammatory cytokines and activation of the immune system is responsible for the progression of several debilitating diseases, such as Psoriasis, Arthritis and Cancer. Initially localised diseases can result in CSI with subsequent systemic spread to distant organs, a key patho-physiological phase responsible for major morbidity and even mortality. Despite the importance of CSI, a complete understanding of the molecular mechanisms, signalling pathways and cell types involved, as well as the chronological evolution of the systemic inflammatory response is still elusive. The classical approach to study inflammation has focused on investigating individual cell types or organs in the pathogenesis of a single disease, thereby neglecting important organ cross-talk and systemic interactions. Furthermore, understanding the temporal and spatial kinetics modulating the inflammatory response requires a detailed study of interactions between different immune and non-immune organs at various time points during disease progression in the context of the whole organism.
The aim of this research proposal is to substantially advance our understanding of whole organ physiology in relation to systemic inflammation as a cause or/and consequence of disease with the focus on Psoriasis/Joint Diseases and Cancer Cachexia. The goal is to elucidate the molecular mechanisms at the cellular and systemic level, and to decipher endocrine interactions and cross-talks between distant organs. Various model systems ranging from cell cultures to genetically engineered mouse models to human clinical samples will be employed. Genomic, proteomic and metabolomic data will be combined with functional in vivo assessment using mouse models to understand the multi-faceted role of systemic inflammation in chronic human diseases, such as Inflammatory Skin/Joint disease and Cachexia, a deadly systemic manifestation of Cancer.
Max ERC Funding
2 499 875 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym HAPLOID
Project “Yeast” genetics in mammalian cells to identify fundamental mechanisms of physiology and pathophysiology
Researcher (PI) Josef Penninger
Host Institution (HI) INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary "Some organisms such as yeast or social insects are haploid, i.e. they carry a single set of chromosomes. Organisms with a single copy of their genome provide a basis for genetic analyses where any recessive mutation of essential genes will show a clear phenotype due to the absence of a second gene copy. Recessive genetic screens have markedly contributed to our understanding of normal development, basic physiology, and disease. However, all somatic mammalian cells carry two copies of chromosomes (diploidy) that obscure mutational screens. Although deemed impossible, we were able to develop generate mammalian haploid embryonic stem cells, thereby breaking a paradigm of biology.
Our novel stem opens the possibility of combining the power of a haploid genome with pluripotency of embryonic stem cells to uncover fundamental biological processes in defined cell types at a genomic scale. The following projects are proposed:
1. Towards“yeast” genetics in mammalian stem cells. Development of optimized technologies for rapid, genome-wide screens via repairable mutagenesis. Mutational bar-coding to introduce quantitative genomics to mammalian biology.
2. Forward genetic screens to uncover essential stem cell genes, identify novel stemness factors, develop improved systems for iPS cell derivation, and to perform synthetic lethal screens for anti-cancer drugs.
3. Reverse genetics using to identify and validate genes involved in cardiovascular physiology, brown and white fat cell development, and pain sensing.
4. Hit validation – exemplified by resistance to the bioweapon ricin.
Haploid embryonic stem cells carry the promise to revolutionize functional genetics and allow rapid, near whole genome-wide mutational forward genetics analysis and reverse genetics in defined cell types. Our systems will be made available to all researchers and the knowledge gained from our studies should fundamentally impact on the basic understanding of physiology and disease pathogenesis."
Summary
"Some organisms such as yeast or social insects are haploid, i.e. they carry a single set of chromosomes. Organisms with a single copy of their genome provide a basis for genetic analyses where any recessive mutation of essential genes will show a clear phenotype due to the absence of a second gene copy. Recessive genetic screens have markedly contributed to our understanding of normal development, basic physiology, and disease. However, all somatic mammalian cells carry two copies of chromosomes (diploidy) that obscure mutational screens. Although deemed impossible, we were able to develop generate mammalian haploid embryonic stem cells, thereby breaking a paradigm of biology.
Our novel stem opens the possibility of combining the power of a haploid genome with pluripotency of embryonic stem cells to uncover fundamental biological processes in defined cell types at a genomic scale. The following projects are proposed:
1. Towards“yeast” genetics in mammalian stem cells. Development of optimized technologies for rapid, genome-wide screens via repairable mutagenesis. Mutational bar-coding to introduce quantitative genomics to mammalian biology.
2. Forward genetic screens to uncover essential stem cell genes, identify novel stemness factors, develop improved systems for iPS cell derivation, and to perform synthetic lethal screens for anti-cancer drugs.
3. Reverse genetics using to identify and validate genes involved in cardiovascular physiology, brown and white fat cell development, and pain sensing.
4. Hit validation – exemplified by resistance to the bioweapon ricin.
Haploid embryonic stem cells carry the promise to revolutionize functional genetics and allow rapid, near whole genome-wide mutational forward genetics analysis and reverse genetics in defined cell types. Our systems will be made available to all researchers and the knowledge gained from our studies should fundamentally impact on the basic understanding of physiology and disease pathogenesis."
Max ERC Funding
2 499 951 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym LIPIDARRAY
Project Development and application of global lipidomic arrays to inflammatory vascular disease
Researcher (PI) Valerie O'donnell
Host Institution (HI) CARDIFF UNIVERSITY
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary How lipids are regulated on a global scale during vascular inflammation is not known. Thus, a major challenge exists to describe and catalog the total lipidome, in particular enabling the identification of new biologically active lipids, and description of changes. This is analogous to ‘omics’ of DNA, RNA and protein, but instead describing diversity of lipids in tissue samples. Importantly, this would encompass not only knowns, but also the vast number of unknowns that have not yet been catalogued in any study so far. Here, new systems biology approaches that can be applied to many other diseases or samples, and integrated with transcriptomic or proteomic analyses will be developed. These would be used to characterize the global lipidome during differentiation of immune cells, and in ex vivo samples from genomically-characterized inflammatory vascular disease. I hypothesize that development and application of “global lipidomic arrays” will define how lipids are regulated during vascular cell differentiation and inflammation, will identify new markers, and open up new therapeutic strategies.
These aims go beyond the current state of the art, and will be achieved by the following objectives that include novel interdisciplinary concepts and approaches:
1. Develop analytical methodologies using Fourier transform mass spectrometry and bioinformatics.
2. Develop approaches for structural identification, using high resolution MSn, high sensitivity NMR, and new computational methodologies.
3. Define the size and diversity of the mammalian cellular lipidome in human platelets (validation).
4. Characterize the global lipidome in (i) monocytes during differentiation from stem /yolk cells to resident, inflammatory or foam cells, (ii) plasma from samples genomically characterized for 14 separate risk alleles for cardiovascular and Alzheimer’s disease.
5. Develop an open access web-based resource for storage and curation of the results to allow others to mine the data.
Summary
How lipids are regulated on a global scale during vascular inflammation is not known. Thus, a major challenge exists to describe and catalog the total lipidome, in particular enabling the identification of new biologically active lipids, and description of changes. This is analogous to ‘omics’ of DNA, RNA and protein, but instead describing diversity of lipids in tissue samples. Importantly, this would encompass not only knowns, but also the vast number of unknowns that have not yet been catalogued in any study so far. Here, new systems biology approaches that can be applied to many other diseases or samples, and integrated with transcriptomic or proteomic analyses will be developed. These would be used to characterize the global lipidome during differentiation of immune cells, and in ex vivo samples from genomically-characterized inflammatory vascular disease. I hypothesize that development and application of “global lipidomic arrays” will define how lipids are regulated during vascular cell differentiation and inflammation, will identify new markers, and open up new therapeutic strategies.
These aims go beyond the current state of the art, and will be achieved by the following objectives that include novel interdisciplinary concepts and approaches:
1. Develop analytical methodologies using Fourier transform mass spectrometry and bioinformatics.
2. Develop approaches for structural identification, using high resolution MSn, high sensitivity NMR, and new computational methodologies.
3. Define the size and diversity of the mammalian cellular lipidome in human platelets (validation).
4. Characterize the global lipidome in (i) monocytes during differentiation from stem /yolk cells to resident, inflammatory or foam cells, (ii) plasma from samples genomically characterized for 14 separate risk alleles for cardiovascular and Alzheimer’s disease.
5. Develop an open access web-based resource for storage and curation of the results to allow others to mine the data.
Max ERC Funding
2 969 345 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym LipoCheX
Project The Role of Lipolysis in the Pathogenesis of
Cancer-associated Cachexia
Researcher (PI) Rudolf Zechner
Host Institution (HI) UNIVERSITAET GRAZ
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary Cachexia is a complex syndrome characterized by massive loss of body weight due to uncontrolled loss of adipose tissue and skeletal muscle. The wasting occurs during late stages of many unrelated chronic diseases and frequently leads to the death of affected individuals. Cachexia is most common in cancer, where an estimated 25% of patients die from cancer-associated cachexia (CAC) rather than from the cancer. Despite the tremendous impact of CAC on morbidity and mortality, the underlying molecular mechanisms are poorly understood.
Recently, we demonstrated that lipase-catalyzed triacylglycerol (TG) catabolism is required for the pathogenesis of CAC. Mice lacking adipose triglyceride lipase, the rate-limiting enzyme for TG hydrolysis (lipolysis), were completely protected from loss of both adipose tissue and muscle in two forms of cancer. This implies an essential role of the lipolytic process in the pathogenesis of CAC. Here we propose to elucidate the causal role of lipases and their coregulators in CAC development. We will determine mechanisms involved and pursue novel treatment strategies.
Our objectives are to:
- Investigate how different cancers in mice regulate tissue-specific lipolysis;
- Elucidate the functional role of lipases and their coregulators in the pathogenesis of CAC;
- Assess whether pharmacological inhibition of specific lipases prevents or delays CAC;
- Study the effects of cancer-induced lipolysis on energy dissipating pathways and epigenetic control.
The project enters a largely unexplored field: the role of lipid metabolism in the pathogenesis of CAC. The work will heavily rely on the characterization of induced mutant mouse models with CAC and require extensive collaboration with experts in pathology and large-scale systems analytics. The results are expected to yield new mechanisms of disease development and provide novel therapeutic targets to prevent the devastating and prevalent consequences of CAC.
Summary
Cachexia is a complex syndrome characterized by massive loss of body weight due to uncontrolled loss of adipose tissue and skeletal muscle. The wasting occurs during late stages of many unrelated chronic diseases and frequently leads to the death of affected individuals. Cachexia is most common in cancer, where an estimated 25% of patients die from cancer-associated cachexia (CAC) rather than from the cancer. Despite the tremendous impact of CAC on morbidity and mortality, the underlying molecular mechanisms are poorly understood.
Recently, we demonstrated that lipase-catalyzed triacylglycerol (TG) catabolism is required for the pathogenesis of CAC. Mice lacking adipose triglyceride lipase, the rate-limiting enzyme for TG hydrolysis (lipolysis), were completely protected from loss of both adipose tissue and muscle in two forms of cancer. This implies an essential role of the lipolytic process in the pathogenesis of CAC. Here we propose to elucidate the causal role of lipases and their coregulators in CAC development. We will determine mechanisms involved and pursue novel treatment strategies.
Our objectives are to:
- Investigate how different cancers in mice regulate tissue-specific lipolysis;
- Elucidate the functional role of lipases and their coregulators in the pathogenesis of CAC;
- Assess whether pharmacological inhibition of specific lipases prevents or delays CAC;
- Study the effects of cancer-induced lipolysis on energy dissipating pathways and epigenetic control.
The project enters a largely unexplored field: the role of lipid metabolism in the pathogenesis of CAC. The work will heavily rely on the characterization of induced mutant mouse models with CAC and require extensive collaboration with experts in pathology and large-scale systems analytics. The results are expected to yield new mechanisms of disease development and provide novel therapeutic targets to prevent the devastating and prevalent consequences of CAC.
Max ERC Funding
2 499 446 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
