Project acronym BrainEnergy
Project Control of cerebral blood flow by capillary pericytes in health and disease
Researcher (PI) David ATTWELL
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Advanced Grant (AdG), LS5, ERC-2016-ADG
Summary Pericytes, located at intervals along capillaries, have recently been revealed as major controllers of brain blood flow. Normally, they dilate capillaries in response to neuronal activity, increasing local blood flow and energy supply. But in pathology they have a more sinister role. After artery block causes a stroke, the brain suffers from the so-called “no-reflow” phenomenon - a failure to fully reperfuse capillaries, even after the upstream occluded artery has been reperfused successfully. The resulting long-lasting decrease of energy supply damages neurons. I have shown that a major cause of no-reflow lies in pericytes: during ischaemia they constrict and then die in rigor. This reduces capillary diameter and blood flow, and probably degrades blood-brain barrier function. However, despite their crucial role in regulating blood flow physiologically and in pathology, little is known about the mechanisms by which pericytes function.
By using blood vessel imaging, patch-clamping, two-photon imaging, optogenetics, immunohistochemistry, mathematical modelling, and live human tissue obtained from neurosurgery, this programme of research will:
(i) define the signalling mechanisms controlling capillary constriction and dilation in health and disease;
(ii) identify the relative contributions of neurons, astrocytes and microglia to regulating pericyte tone;
(iii) develop approaches to preventing brain pericyte constriction and death during ischaemia;
(iv) define how pericyte constriction of capillaries and pericyte death contribute to Alzheimer’s disease;
(v) extend these results from rodent brain to human brain pericytes as a prelude to developing therapies.
The diseases to which pericytes contribute include stroke, spinal cord injury, diabetes and Alzheimer’s disease. These all have an enormous economic impact, as well as causing great suffering for patients and their carers. This work will provide novel therapeutic approaches for treating these diseases.
Summary
Pericytes, located at intervals along capillaries, have recently been revealed as major controllers of brain blood flow. Normally, they dilate capillaries in response to neuronal activity, increasing local blood flow and energy supply. But in pathology they have a more sinister role. After artery block causes a stroke, the brain suffers from the so-called “no-reflow” phenomenon - a failure to fully reperfuse capillaries, even after the upstream occluded artery has been reperfused successfully. The resulting long-lasting decrease of energy supply damages neurons. I have shown that a major cause of no-reflow lies in pericytes: during ischaemia they constrict and then die in rigor. This reduces capillary diameter and blood flow, and probably degrades blood-brain barrier function. However, despite their crucial role in regulating blood flow physiologically and in pathology, little is known about the mechanisms by which pericytes function.
By using blood vessel imaging, patch-clamping, two-photon imaging, optogenetics, immunohistochemistry, mathematical modelling, and live human tissue obtained from neurosurgery, this programme of research will:
(i) define the signalling mechanisms controlling capillary constriction and dilation in health and disease;
(ii) identify the relative contributions of neurons, astrocytes and microglia to regulating pericyte tone;
(iii) develop approaches to preventing brain pericyte constriction and death during ischaemia;
(iv) define how pericyte constriction of capillaries and pericyte death contribute to Alzheimer’s disease;
(v) extend these results from rodent brain to human brain pericytes as a prelude to developing therapies.
The diseases to which pericytes contribute include stroke, spinal cord injury, diabetes and Alzheimer’s disease. These all have an enormous economic impact, as well as causing great suffering for patients and their carers. This work will provide novel therapeutic approaches for treating these diseases.
Max ERC Funding
2 499 954 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
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 HippoKAR
Project Understanding the roles of kainate receptors in the hippocampus
Researcher (PI) Graham Leon Collingridge
Host Institution (HI) UNIVERSITY OF BRISTOL
Call Details Advanced Grant (AdG), LS5, ERC-2013-ADG
Summary Kainate receptors (KARs) are often regarded as the last frontier of glutamate receptor research, since much less is known about their physiological roles compared with that of the other glutamate receptor subtypes. This field of research is very important not just because of the unique role that KARs play in neuronal function, including specific forms of synaptic plasticity, but because of the increasing evidence that KARs are involved in a plethora of brain diseases and that KAR antagonists are promising novel therapeutic targets. I propose to lead a highly multidisciplinary approach, in collaboration with colleagues at Bristol and strategic collaborators worldwide, to develop novel pharmacological and genetic tools, which will be rapidly disseminated to the neuroscience community. These tools will be used here to test hypotheses regarding functions of KARs in granule cells (GCs) in the dentate gyrus of the hippocampal formation, with a focus on mossy fibre long-term potentiation (LTP). We propose four interrelated objectives: (i) to develop potent and selective antagonists for the GluK2 subunit of KARs, (ii) to generate GC specific knockouts of the five KAR subunits, by floxing GluK1-5 and crossing with a GC-specific Cre recombinase mouse line, (iii) to use these and existing tools in a combined pharmacological and genetic approach, to understand the functions of KARs at mossy fibre synapses in acute and organotypic hippocampal slices. A new development will be to record simultaneously from synaptically coupled GC-CA3 neuronal pairs and to image Ca2+ from participating mossy fibre boutons, (iv) to extend these investigations to the study of mossy fibre function, in particular LTP, in anaesthetised animals and to establish the function of mossy fibre LTP in hippocampus-dependent learning and memory. Although highly ambitious, the proposal is based on a long track record of KAR research by the PI and his collaborators plus a substantial amount of preliminary data.
Summary
Kainate receptors (KARs) are often regarded as the last frontier of glutamate receptor research, since much less is known about their physiological roles compared with that of the other glutamate receptor subtypes. This field of research is very important not just because of the unique role that KARs play in neuronal function, including specific forms of synaptic plasticity, but because of the increasing evidence that KARs are involved in a plethora of brain diseases and that KAR antagonists are promising novel therapeutic targets. I propose to lead a highly multidisciplinary approach, in collaboration with colleagues at Bristol and strategic collaborators worldwide, to develop novel pharmacological and genetic tools, which will be rapidly disseminated to the neuroscience community. These tools will be used here to test hypotheses regarding functions of KARs in granule cells (GCs) in the dentate gyrus of the hippocampal formation, with a focus on mossy fibre long-term potentiation (LTP). We propose four interrelated objectives: (i) to develop potent and selective antagonists for the GluK2 subunit of KARs, (ii) to generate GC specific knockouts of the five KAR subunits, by floxing GluK1-5 and crossing with a GC-specific Cre recombinase mouse line, (iii) to use these and existing tools in a combined pharmacological and genetic approach, to understand the functions of KARs at mossy fibre synapses in acute and organotypic hippocampal slices. A new development will be to record simultaneously from synaptically coupled GC-CA3 neuronal pairs and to image Ca2+ from participating mossy fibre boutons, (iv) to extend these investigations to the study of mossy fibre function, in particular LTP, in anaesthetised animals and to establish the function of mossy fibre LTP in hippocampus-dependent learning and memory. Although highly ambitious, the proposal is based on a long track record of KAR research by the PI and his collaborators plus a substantial amount of preliminary data.
Max ERC Funding
2 500 000 €
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
