Project acronym ANTILEAK
Project Development of antagonists of vascular leakage
Researcher (PI) Pipsa SAHARINEN
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Consolidator Grant (CoG), LS4, ERC-2017-COG
Summary Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.
Summary
Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.
Max ERC Funding
1 999 770 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym Brain Health Toolbox
Project The Brain Health Toolbox: Facilitating personalized decision-making for effective dementia prevention
Researcher (PI) Alina Gabriela SOLOMON
Host Institution (HI) ITA-SUOMEN YLIOPISTO
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary Preventing dementia and Alzheimer disease (AD) is a global priority. Previous single-intervention failures stress the critical need for a new multimodal preventive approach in these complex multifactorial conditions. The Brain Health Toolbox is designed to create a seamless continuum from accurate dementia prediction to effective prevention by i) developing the missing disease models and prediction tools for multimodal prevention; ii) testing them in actual multimodal prevention trials; and iii) bridging the gap between non-pharmacological and pharmacological approaches by designing a combined multimodal prevention trial based on a new European adaptive trial platform. Disease models and prediction tools will be multi-dimensional, i.e. a broad range of risk factors and biomarker types, including novel markers. An innovative machine learning method will be used for pattern identification and risk profiling to highlight most important contributors to an individual’s overall risk level. This is crucial for early identification of individuals with high dementia risk and/or high likelihood of specific brain pathologies, quantifying an individual’s prevention potential, and longitudinal risk and disease monitoring, also beyond trial duration. Three Toolbox test scenarios are considered: use for selecting target populations, assessing heterogeneity of intervention effects, and use as trial outcome. The project is based on a unique set-up aligning several new multimodal lifestyle trials aiming to adapt and test non-pharmacological interventions to different geographic, economic and cultural settings, with two reference libraries (observational - large datasets; and interventional - four recently completed pioneering multimodal lifestyle prevention trials). The Brain Health Toolbox covers the entire continuum from general populations to patients with preclinical/prodromal disease stages, and will provide tools for personalized decision-making for dementia prevention.
Summary
Preventing dementia and Alzheimer disease (AD) is a global priority. Previous single-intervention failures stress the critical need for a new multimodal preventive approach in these complex multifactorial conditions. The Brain Health Toolbox is designed to create a seamless continuum from accurate dementia prediction to effective prevention by i) developing the missing disease models and prediction tools for multimodal prevention; ii) testing them in actual multimodal prevention trials; and iii) bridging the gap between non-pharmacological and pharmacological approaches by designing a combined multimodal prevention trial based on a new European adaptive trial platform. Disease models and prediction tools will be multi-dimensional, i.e. a broad range of risk factors and biomarker types, including novel markers. An innovative machine learning method will be used for pattern identification and risk profiling to highlight most important contributors to an individual’s overall risk level. This is crucial for early identification of individuals with high dementia risk and/or high likelihood of specific brain pathologies, quantifying an individual’s prevention potential, and longitudinal risk and disease monitoring, also beyond trial duration. Three Toolbox test scenarios are considered: use for selecting target populations, assessing heterogeneity of intervention effects, and use as trial outcome. The project is based on a unique set-up aligning several new multimodal lifestyle trials aiming to adapt and test non-pharmacological interventions to different geographic, economic and cultural settings, with two reference libraries (observational - large datasets; and interventional - four recently completed pioneering multimodal lifestyle prevention trials). The Brain Health Toolbox covers the entire continuum from general populations to patients with preclinical/prodromal disease stages, and will provide tools for personalized decision-making for dementia prevention.
Max ERC Funding
1 498 268 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym CANCER SIGNALOSOMES
Project Spatially and temporally regulated membrane complexes in cancer cell invasion and cytokinesis
Researcher (PI) Johanna Ivaska
Host Institution (HI) TEKNOLOGIAN TUTKIMUSKESKUS VTT
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary Cancer progression, characterized by uncontrolled proliferation and motility of cells, is a complex and deadly process. Integrins, a major cell surface adhesion receptor family, are transmembrane proteins known to regulate cell behaviour by transducing extracellular signals to cytoplasmic protein complexes. We and others have shown that recruitment of specific protein complexes by the cytoplasmic domains of integrins is important in tumorigenesis. Here our aim is to study three interrelated processes in cancer progression which involve integrin signalling, but which have not been elucidated earlier at all. 1) Integrins in cell division (cytokinesis). Since coordinated action of the cytoskeleton and membranes is needed both for cell division and motility, shared integrin functions can regulate both events. 2) Dynamic integrin signalosomes at the leading edge of invading cells. Spatially and temporally regulated, integrin-protein complexes at the front of infiltrating cells are likely to dictate the movement of cancer cells in tissues. 3) Transmembrane segments of integrins as scaffolds for integrin signalling. In addition to cytosolic proteins, integrins most likely interact with proteins within the membrane resulting into new signalling modalities. In this proposal we will use innovative, modern and even unconventional techniques (such as RNAi and live-cell arrays detecting integrin traffic, cell motility and multiplication, laser-microdissection, proteomics and bacterial-two-hybrid screens) to unravel these new integrin functions, for which we have preliminary evidence. Each project will give fundamentally novel mechanistic insight into the role of integrins in cancer. Moreover, these interdisciplinary new openings will increase our understanding in cancer progression in general and will open new possibilities for therapeutic intervention targeting both cancer proliferation and dissemination in the body.
Summary
Cancer progression, characterized by uncontrolled proliferation and motility of cells, is a complex and deadly process. Integrins, a major cell surface adhesion receptor family, are transmembrane proteins known to regulate cell behaviour by transducing extracellular signals to cytoplasmic protein complexes. We and others have shown that recruitment of specific protein complexes by the cytoplasmic domains of integrins is important in tumorigenesis. Here our aim is to study three interrelated processes in cancer progression which involve integrin signalling, but which have not been elucidated earlier at all. 1) Integrins in cell division (cytokinesis). Since coordinated action of the cytoskeleton and membranes is needed both for cell division and motility, shared integrin functions can regulate both events. 2) Dynamic integrin signalosomes at the leading edge of invading cells. Spatially and temporally regulated, integrin-protein complexes at the front of infiltrating cells are likely to dictate the movement of cancer cells in tissues. 3) Transmembrane segments of integrins as scaffolds for integrin signalling. In addition to cytosolic proteins, integrins most likely interact with proteins within the membrane resulting into new signalling modalities. In this proposal we will use innovative, modern and even unconventional techniques (such as RNAi and live-cell arrays detecting integrin traffic, cell motility and multiplication, laser-microdissection, proteomics and bacterial-two-hybrid screens) to unravel these new integrin functions, for which we have preliminary evidence. Each project will give fundamentally novel mechanistic insight into the role of integrins in cancer. Moreover, these interdisciplinary new openings will increase our understanding in cancer progression in general and will open new possibilities for therapeutic intervention targeting both cancer proliferation and dissemination in the body.
Max ERC Funding
1 529 369 €
Duration
Start date: 2008-08-01, End date: 2013-07-31
Project acronym COMPLEX-FISH
Project Complex eco-evolutionary dynamics of aquatic ecosystems faced with human-induced and environmental stress
Researcher (PI) Anna KUPARINEN
Host Institution (HI) JYVASKYLAN YLIOPISTO
Call Details Consolidator Grant (CoG), LS8, ERC-2017-COG
Summary Resilience and recovery ability are key determinants of species persistence and viability in a changing world. Populations exposed to rapid environmental changes and human-induced alterations are often affected by both ecological and evolutionary processes and their interactions, that is, eco-evolutionary dynamics. The integrated perspective offered by eco-evolutionary dynamics is vital for understanding drivers of resilience and recovery of natural populations undergoing rapid changes and exposed to multiple stressors. However, the feedback mechanisms, and the ways in which evolution and phenotypic changes scale up to interacting species, communities, and ecosystems, remains poorly understood. The objective of my proposal is to bridge and close this gap by merging the fields of ecology and evolution into two interfaces of complex biological dynamics. I will do this in the context of conservation and sustainable harvesting of aquatic ecosystems. I will develop a novel mechanistic theory of eco-evolutionary ecosystem dynamics, by coupling the theory of allometric trophic networks with the theory of life-history evolution. I will analyse the eco-evolutionary dynamics of aquatic ecosystems to identify mechanisms responsible for species and ecosystem resilience and recovery ability. This will be done through systematic simulation studies and detailed analyses of three aquatic ecosystems. The project delves into the mechanisms through which anthropogenic and environmental drivers alter the eco-evolutionary dynamics of aquatic ecosystems. Mechanistic understanding of these dynamics, and their consequences to species and ecosystems, has great potential to resolve fundamental yet puzzling patterns observed in natural populations and to identify species and ecosystem properties regulating resilience and recovery ability. This will drastically change our ability to assess the risks related to current and future anthropogenic and environmental influences on aquatic ecosystems.
Summary
Resilience and recovery ability are key determinants of species persistence and viability in a changing world. Populations exposed to rapid environmental changes and human-induced alterations are often affected by both ecological and evolutionary processes and their interactions, that is, eco-evolutionary dynamics. The integrated perspective offered by eco-evolutionary dynamics is vital for understanding drivers of resilience and recovery of natural populations undergoing rapid changes and exposed to multiple stressors. However, the feedback mechanisms, and the ways in which evolution and phenotypic changes scale up to interacting species, communities, and ecosystems, remains poorly understood. The objective of my proposal is to bridge and close this gap by merging the fields of ecology and evolution into two interfaces of complex biological dynamics. I will do this in the context of conservation and sustainable harvesting of aquatic ecosystems. I will develop a novel mechanistic theory of eco-evolutionary ecosystem dynamics, by coupling the theory of allometric trophic networks with the theory of life-history evolution. I will analyse the eco-evolutionary dynamics of aquatic ecosystems to identify mechanisms responsible for species and ecosystem resilience and recovery ability. This will be done through systematic simulation studies and detailed analyses of three aquatic ecosystems. The project delves into the mechanisms through which anthropogenic and environmental drivers alter the eco-evolutionary dynamics of aquatic ecosystems. Mechanistic understanding of these dynamics, and their consequences to species and ecosystems, has great potential to resolve fundamental yet puzzling patterns observed in natural populations and to identify species and ecosystem properties regulating resilience and recovery ability. This will drastically change our ability to assess the risks related to current and future anthropogenic and environmental influences on aquatic ecosystems.
Max ERC Funding
1 999 391 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym CORKtheCAMBIA
Project Thickening of plant organs by nested stem cells
Researcher (PI) Ari Pekka MÄHÖNEN
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Consolidator Grant (CoG), LS3, ERC-2018-COG
Summary Growth originates from meristems, where stem cells are located. Lateral meristems, which provide thickness to tree stems and other plant organs, include vascular cambium (produces xylem [wood] and phloem); and cork cambium (forms cork, a tough protective layer).
We recently identified the molecular mechanism that specifies stem cells of vascular cambium. Unexpectedly, this same set of experiments revealed also novel aspects of the regulation of cork cambium, a meristem whose development has remained unknown. CORKtheCAMBIA aims to identify the stem cells of cork cambium and reveal how they mechanistically regulate plant organ thickening. Thus, stemming from these novel unpublished findings and my matching expertise on plant stem cells and lateral growth, the timing is perfect to discover the molecular mechanism underlying specification of stem cells of cork cambium.
To identify the origin of stem cells of cork cambium, 1st-we will combine lineage tracing with a detailed molecular marker analysis. To deduce the cell dynamics of cork cambium, 2nd-we will follow regeneration of the stem cells after ablation of this meristem. To discover the molecular factors regulating the stem cell specification of cork cambium, 3rd-we will utilize molecular genetics and a novel method (inducible CRISPR/Cas9 mutant targeting) being developed in my lab. Since the lateral growth is orchestrated by two adjacent, nested meristems, cork and vascular cambia, the growth process must be tightly co-regulated. Thus, 4th-an in silico model of the intertwined growth process will be generated. By combining modelling with experimentation, we will uncover mechanistically how cork and vascular cambium coordinate lateral growth.
CORKtheCAMBIA will thus provide long-awaited insight into the regulatory mechanisms specifying the stem cells of lateral meristem as whole, lay the foundation for studies on radial thickening and facilitate rational manipulation of lateral meristems of crop plants and trees.
Summary
Growth originates from meristems, where stem cells are located. Lateral meristems, which provide thickness to tree stems and other plant organs, include vascular cambium (produces xylem [wood] and phloem); and cork cambium (forms cork, a tough protective layer).
We recently identified the molecular mechanism that specifies stem cells of vascular cambium. Unexpectedly, this same set of experiments revealed also novel aspects of the regulation of cork cambium, a meristem whose development has remained unknown. CORKtheCAMBIA aims to identify the stem cells of cork cambium and reveal how they mechanistically regulate plant organ thickening. Thus, stemming from these novel unpublished findings and my matching expertise on plant stem cells and lateral growth, the timing is perfect to discover the molecular mechanism underlying specification of stem cells of cork cambium.
To identify the origin of stem cells of cork cambium, 1st-we will combine lineage tracing with a detailed molecular marker analysis. To deduce the cell dynamics of cork cambium, 2nd-we will follow regeneration of the stem cells after ablation of this meristem. To discover the molecular factors regulating the stem cell specification of cork cambium, 3rd-we will utilize molecular genetics and a novel method (inducible CRISPR/Cas9 mutant targeting) being developed in my lab. Since the lateral growth is orchestrated by two adjacent, nested meristems, cork and vascular cambia, the growth process must be tightly co-regulated. Thus, 4th-an in silico model of the intertwined growth process will be generated. By combining modelling with experimentation, we will uncover mechanistically how cork and vascular cambium coordinate lateral growth.
CORKtheCAMBIA will thus provide long-awaited insight into the regulatory mechanisms specifying the stem cells of lateral meristem as whole, lay the foundation for studies on radial thickening and facilitate rational manipulation of lateral meristems of crop plants and trees.
Max ERC Funding
1 999 752 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym CUMTAS
Project Customized Micro Total Analysis Systems to Study Human Phase I Metabolism
Researcher (PI) Tiina Marjukka Sikanen
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), LS9, ERC-2012-StG_20111109
Summary The goal of this project is to develop inexpensive, high-throughput technology to screen the thus far unexplored metabolic interactions between environmental and household chemicals and clinically relevant drugs. The main influential focus will be on human phase I metabolism (redox reactions) of common toxicants like agrochemicals and plasticizers. On the basis of their structural resemblance to pharmaceuticals and endogenous compounds, many of these chemicals are suspected to have critical effects on cytochrome P450 metabolism which is the main detoxification route of pharmaceuticals in man. However, with the current analytical instrumentation, screening of such large chemical pool would take several years, and new chemicals would be introduced faster than the old ones are screened. Thus, the main technological goal of this project is to develop novel, practically zero-cost analytical instruments that enable characterization of a compound’s metabolic profile at very high speed (<1 min/sample). This goal is achieved through miniaturization and high degree of integration of analytical instrumentation by microfabrication means, an approach often called lab(oratory)-on-a-chip. The microfabricated arrays are envisioned to incorporate all analytical key functions required (i.e., sample pretreatment, metabolic reaction, separation of the reaction products, detection) on a single chip. Thanks to the reduced dimensions, the amount of chemical waste and consumption of expensive reagents are significantly reduced. In this project, several different microfabrication techniques, from delicate cleanroom processes to extremely simple printing techniques, will be exploited to produce smart microfluidic designs and multifunctional surfaces. Towards the end of the project, more focus will be put on “printable microfluidics” which provides a truly low-cost approach for fabrication of highly customized microfluidic assays. Numerical modelling is also an integral part of the work.
Summary
The goal of this project is to develop inexpensive, high-throughput technology to screen the thus far unexplored metabolic interactions between environmental and household chemicals and clinically relevant drugs. The main influential focus will be on human phase I metabolism (redox reactions) of common toxicants like agrochemicals and plasticizers. On the basis of their structural resemblance to pharmaceuticals and endogenous compounds, many of these chemicals are suspected to have critical effects on cytochrome P450 metabolism which is the main detoxification route of pharmaceuticals in man. However, with the current analytical instrumentation, screening of such large chemical pool would take several years, and new chemicals would be introduced faster than the old ones are screened. Thus, the main technological goal of this project is to develop novel, practically zero-cost analytical instruments that enable characterization of a compound’s metabolic profile at very high speed (<1 min/sample). This goal is achieved through miniaturization and high degree of integration of analytical instrumentation by microfabrication means, an approach often called lab(oratory)-on-a-chip. The microfabricated arrays are envisioned to incorporate all analytical key functions required (i.e., sample pretreatment, metabolic reaction, separation of the reaction products, detection) on a single chip. Thanks to the reduced dimensions, the amount of chemical waste and consumption of expensive reagents are significantly reduced. In this project, several different microfabrication techniques, from delicate cleanroom processes to extremely simple printing techniques, will be exploited to produce smart microfluidic designs and multifunctional surfaces. Towards the end of the project, more focus will be put on “printable microfluidics” which provides a truly low-cost approach for fabrication of highly customized microfluidic assays. Numerical modelling is also an integral part of the work.
Max ERC Funding
1 499 668 €
Duration
Start date: 2013-05-01, End date: 2019-02-28
Project acronym EnDeCAD
Project Enhancers Decoding the Mechanisms Underlying CAD Risk
Researcher (PI) Minna Unelma KAIKKONEN-MÄÄTTÄ
Host Institution (HI) ITA-SUOMEN YLIOPISTO
Call Details Starting Grant (StG), LS4, ERC-2018-STG
Summary In recent years, genome-wide association studies (GWAS) have discovered hundreds of single nucleotide polymorphisms (SNPs) which are significantly associated with coronary artery disease (CAD). However, the SNPs identified by GWAS explain typically only small portion of the trait heritability and vast majority of variants do not have known biological roles. This is explained by variants lying within noncoding regions such as in cell type specific enhancers and additionally ‘the lead SNP’ identified in GWAS may not be the ‘the causal SNP’ but only linked with a trait associated SNP. Therefore, a major priority for understanding disease mechanisms is to understand at the molecular level the function of each CAD loci. In this study we aim to bring the functional characterization of SNPs associated with CAD risk to date by focusing our search for causal SNPs to enhancers of disease relevant cell types, namely endothelial cells, macrophages and smooth muscle cells of the vessel wall, hepatocytes and adipocytes. By combination of massively parallel enhancer activity measurements, collection of novel eQTL data throughout cell types under disease relevant stimuli, identification of the target genes in physical interaction with the candidate enhancers and establishment of correlative relationships between enhancer activity and gene expression we hope to identify causal enhancer variants and link them with target genes to obtain a more complete picture of the gene regulatory events driving disease progression and the genetic basis of CAD. Linking these findings with our deep phenotypic data for cardiovascular risk factors, gene expression and metabolomics has the potential to improve risk prediction, biomarker identification and treatment selection in clinical practice. Ultimately, this research strives for fundamental discoveries and breakthrough that advance our knowledge of CAD and provides pioneering steps towards taking the growing array of GWAS for translatable results.
Summary
In recent years, genome-wide association studies (GWAS) have discovered hundreds of single nucleotide polymorphisms (SNPs) which are significantly associated with coronary artery disease (CAD). However, the SNPs identified by GWAS explain typically only small portion of the trait heritability and vast majority of variants do not have known biological roles. This is explained by variants lying within noncoding regions such as in cell type specific enhancers and additionally ‘the lead SNP’ identified in GWAS may not be the ‘the causal SNP’ but only linked with a trait associated SNP. Therefore, a major priority for understanding disease mechanisms is to understand at the molecular level the function of each CAD loci. In this study we aim to bring the functional characterization of SNPs associated with CAD risk to date by focusing our search for causal SNPs to enhancers of disease relevant cell types, namely endothelial cells, macrophages and smooth muscle cells of the vessel wall, hepatocytes and adipocytes. By combination of massively parallel enhancer activity measurements, collection of novel eQTL data throughout cell types under disease relevant stimuli, identification of the target genes in physical interaction with the candidate enhancers and establishment of correlative relationships between enhancer activity and gene expression we hope to identify causal enhancer variants and link them with target genes to obtain a more complete picture of the gene regulatory events driving disease progression and the genetic basis of CAD. Linking these findings with our deep phenotypic data for cardiovascular risk factors, gene expression and metabolomics has the potential to improve risk prediction, biomarker identification and treatment selection in clinical practice. Ultimately, this research strives for fundamental discoveries and breakthrough that advance our knowledge of CAD and provides pioneering steps towards taking the growing array of GWAS for translatable results.
Max ERC Funding
1 498 647 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym ForceMorph
Project The integration of cell signalling and mechanical forces in vascular morphology
Researcher (PI) Cecilia Maria SAHLGREN
Host Institution (HI) ABO AKADEMI
Call Details Consolidator Grant (CoG), LS9, ERC-2017-COG
Summary Cardiovascular diseases represent the principal worldwide medical challenge of the 21st century (WHO), and new concepts to treat, predict and even prevent these diseases are needed. Structural remodelling of the vasculature in response to changes in blood flow is important to maintain mechanical homeostasis, and many diseases are related to defects in tissue morphology and mechanical imbalance. Signalling between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) via the Notch pathway regulates the morphology and structural remodelling of the arterial wall. Importantly, Notch offers handles for therapeutic control and thus opportunities for treatment of malformation and adaptation. However, we lack the essential understanding of how hemodynamic forces integrate with Notch signalling to rationally and responsibly target Notch in vascular therapies. The complexity of the problem requires new tools and an interdisciplinary approach. Our project integrates engineering, computational modelling, with cell biology and in vivo model systems to address the question. In vivo models will validate the in in vitro model systems to ensure that they are reproducible and reflect the reality. Through this integrated approach we will enable new therapeutic developments.
The specific objectives of the project are to:
1) Study EC-VSMC signalling real time, at high resolution by a novel biomimetic 4D Artery-on-Chip that recapitulates the cell-composition, -organisation and hemodynamic forces of the physiological artery
2) Develop a computational model of the arterial wall that include the mechanosensitivity of Notch signalling to predict how the complex interactions affect arterial morphology and remodelling
3) Use in vivo animal models to elucidate how regulation of Notch signalling affects tissue morphology and remodelling in response to changes in hemodynamic conditions
Summary
Cardiovascular diseases represent the principal worldwide medical challenge of the 21st century (WHO), and new concepts to treat, predict and even prevent these diseases are needed. Structural remodelling of the vasculature in response to changes in blood flow is important to maintain mechanical homeostasis, and many diseases are related to defects in tissue morphology and mechanical imbalance. Signalling between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) via the Notch pathway regulates the morphology and structural remodelling of the arterial wall. Importantly, Notch offers handles for therapeutic control and thus opportunities for treatment of malformation and adaptation. However, we lack the essential understanding of how hemodynamic forces integrate with Notch signalling to rationally and responsibly target Notch in vascular therapies. The complexity of the problem requires new tools and an interdisciplinary approach. Our project integrates engineering, computational modelling, with cell biology and in vivo model systems to address the question. In vivo models will validate the in in vitro model systems to ensure that they are reproducible and reflect the reality. Through this integrated approach we will enable new therapeutic developments.
The specific objectives of the project are to:
1) Study EC-VSMC signalling real time, at high resolution by a novel biomimetic 4D Artery-on-Chip that recapitulates the cell-composition, -organisation and hemodynamic forces of the physiological artery
2) Develop a computational model of the arterial wall that include the mechanosensitivity of Notch signalling to predict how the complex interactions affect arterial morphology and remodelling
3) Use in vivo animal models to elucidate how regulation of Notch signalling affects tissue morphology and remodelling in response to changes in hemodynamic conditions
Max ERC Funding
1 919 599 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym FREEDLES
Project From needles to landscapes: a novel approach to scaling forest spectra
Researcher (PI) Miina Alina RAUTIAINEN
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Call Details Consolidator Grant (CoG), LS9, ERC-2017-COG
Summary Accounting for vegetation structure – clumping of foliage into shoots or crowns – is the largest remaining challenge in modelling scattered and absorbed radiation in complex vegetation canopies such as forests. Clumping controls the radiation regime of forest canopies, yet it is poorly quantified. Currently, the communities working with vegetation structure and optical measurements do not have a common understanding of the concept. The FREEDLES project sets out to develop a universal method for quantifying clumping of foliage in forests based on detailed 3D structure and spectral reflectance data. Clumping will be linked to photon recollision probability, an exciting new development in the field of photon transport modelling. Photon recollision probability will, in turn, be used to develop a spectral scaling algorithm which will connect the spectra of vegetation at all hierarchical levels from needles and leaves to crowns, stands and landscapes. The spectral scaling algorithm will be validated with detailed reference measurements in both laboratory and natural conditions, and applied to interpret forest variables from satellite images at different spatial resolutions. The proposed approach is contrary to many other lines of current development where more complexity is favoured in canopy radiation models. If successful, the approach will significantly improve estimates of absorbed and scattered radiation fields in forests and retrieval results of forest biophysical variables from satellite data. Future applications can also be expected in global radiation and carbon balance estimation and in chlorophyll fluorescence models for forests. Most importantly, the spectral scaling model will open new horizons for our scientific understanding of photon-vegetation interactions.
Summary
Accounting for vegetation structure – clumping of foliage into shoots or crowns – is the largest remaining challenge in modelling scattered and absorbed radiation in complex vegetation canopies such as forests. Clumping controls the radiation regime of forest canopies, yet it is poorly quantified. Currently, the communities working with vegetation structure and optical measurements do not have a common understanding of the concept. The FREEDLES project sets out to develop a universal method for quantifying clumping of foliage in forests based on detailed 3D structure and spectral reflectance data. Clumping will be linked to photon recollision probability, an exciting new development in the field of photon transport modelling. Photon recollision probability will, in turn, be used to develop a spectral scaling algorithm which will connect the spectra of vegetation at all hierarchical levels from needles and leaves to crowns, stands and landscapes. The spectral scaling algorithm will be validated with detailed reference measurements in both laboratory and natural conditions, and applied to interpret forest variables from satellite images at different spatial resolutions. The proposed approach is contrary to many other lines of current development where more complexity is favoured in canopy radiation models. If successful, the approach will significantly improve estimates of absorbed and scattered radiation fields in forests and retrieval results of forest biophysical variables from satellite data. Future applications can also be expected in global radiation and carbon balance estimation and in chlorophyll fluorescence models for forests. Most importantly, the spectral scaling model will open new horizons for our scientific understanding of photon-vegetation interactions.
Max ERC Funding
1 963 590 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym FutureTrophicFactors
Project Elucidating therapeutic effects and mode of action of future trophic factorsin ALS and Parkinson’s disease
Researcher (PI) Merja Hannele VOUTILAINEN
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary The prevalence of neurodegenerative diseases such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) is growing rapidly due to an aging population and increased life expectancy. Current treatments for ALS and PD only relieve symptoms and cannot stop the progression of the disease, thus there is an urgent need for new therapies. Neurotrophic factors (NTFs) are secretary proteins that regulate the survival of neurons, neurite growth and branching. They have been explored as novel drugs for the treatment of ALS and PD but their efficacy in clinical trials is poor. CDNF is a protein with NTF properties that protects and restores the function of dopamine neurons in rodent and rhesus monkey toxin models of PD more effectively than other NTFs. CDNF is currently in phase 1/2 clinical trials on PD patients. Despite promising results with CDNF in animal models of PD, NTF and CDNF-based treatments have drawbacks. CDNF requires direct delivery to the brain through invasive surgery since, it cannot pass through the blood brain barrier (BBB). My recent discovery, however, may overcome this difficulty: I showed that a novel CDNF variant protects DA neurons in vitro and in vivo and that it efficiently enters DA neurons in culture. Furthermore, my data show the CDNF fragment can pass through the BBB as measured by 3 different methods and has a neurorestorative effect in a 6-OHDA toxin model of PD when administered subcutaneously. The ultimate goal of my research is to understand the mode of action and therapeutic effect of novel BBB penetrating CDNF-derived polypeptides in cultures of human induced pluripotent stem (iPS) cell-derived nerve cells from patients and in animal models of ALS and PD. The innovative aspect of this proposal is the new groundbreaking concept for treating neurodegenerative diseases – peripheral delivery of BBB penetrating peptides with trophic factor properties and the potential to treat non-motor and motor symptoms in ALS and PD patients.
Summary
The prevalence of neurodegenerative diseases such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) is growing rapidly due to an aging population and increased life expectancy. Current treatments for ALS and PD only relieve symptoms and cannot stop the progression of the disease, thus there is an urgent need for new therapies. Neurotrophic factors (NTFs) are secretary proteins that regulate the survival of neurons, neurite growth and branching. They have been explored as novel drugs for the treatment of ALS and PD but their efficacy in clinical trials is poor. CDNF is a protein with NTF properties that protects and restores the function of dopamine neurons in rodent and rhesus monkey toxin models of PD more effectively than other NTFs. CDNF is currently in phase 1/2 clinical trials on PD patients. Despite promising results with CDNF in animal models of PD, NTF and CDNF-based treatments have drawbacks. CDNF requires direct delivery to the brain through invasive surgery since, it cannot pass through the blood brain barrier (BBB). My recent discovery, however, may overcome this difficulty: I showed that a novel CDNF variant protects DA neurons in vitro and in vivo and that it efficiently enters DA neurons in culture. Furthermore, my data show the CDNF fragment can pass through the BBB as measured by 3 different methods and has a neurorestorative effect in a 6-OHDA toxin model of PD when administered subcutaneously. The ultimate goal of my research is to understand the mode of action and therapeutic effect of novel BBB penetrating CDNF-derived polypeptides in cultures of human induced pluripotent stem (iPS) cell-derived nerve cells from patients and in animal models of ALS and PD. The innovative aspect of this proposal is the new groundbreaking concept for treating neurodegenerative diseases – peripheral delivery of BBB penetrating peptides with trophic factor properties and the potential to treat non-motor and motor symptoms in ALS and PD patients.
Max ERC Funding
1 497 597 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
