Project acronym CHROMATINMODWEB
Project Functional and regulatory protein networks of chromatin modifying enzymes
Researcher (PI) Antonis Kirmizis
Host Institution (HI) UNIVERSITY OF CYPRUS
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary Proper and controlled expression of genes is essential for normal cell growth. Chromatin modifying enzymes play a
fundamental role in the control of gene expression and their deregulation is often linked to cancer. In recent years chromatin
modifiers have been considered key targets for cancer therapy and this demands a full understanding of their biological
functions. Previous biochemical and structural studies have focused on the identification of chromatin modifying enzymes
and characterization of their substrate specificities and catalytic mechanisms. However, a comprehensive view of the
biological processes, signaling pathways and regulatory circuits in which these enzymes participate is missing. Protein
arginine methyltransferases (PRMTs), which methylate histones and are evolutionarily conserved from yeast to human,
constitute an example of chromatin modifying enzymes whose functional and regulatory networks remain unexplored. I
propose to use complementary state-of-the-art genomic and proteomic approaches in order to identify the protein networks
and cellular pathways that are linked to PRMTs. In parallel, I will identify novel regulatory circuits and define the molecular
mechanisms that control methylation of specific histone arginine residues. I will utilize the yeast S. cerevisiae as a model
organism because it allows genetic, biochemical and genomic approaches to be combined. Most importantly, many of the
pathways and mechanisms in yeast are highly conserved and therefore, the findings from this study will be pertinent to
human and other eukaryotic organisms. Establishing a global cellular wiring diagram of PRMTs will serve as a paradigm for
other chromatin modifiers and is imperative for assessing the efficacy of these enzymes as therapeutic targets.
Summary
Proper and controlled expression of genes is essential for normal cell growth. Chromatin modifying enzymes play a
fundamental role in the control of gene expression and their deregulation is often linked to cancer. In recent years chromatin
modifiers have been considered key targets for cancer therapy and this demands a full understanding of their biological
functions. Previous biochemical and structural studies have focused on the identification of chromatin modifying enzymes
and characterization of their substrate specificities and catalytic mechanisms. However, a comprehensive view of the
biological processes, signaling pathways and regulatory circuits in which these enzymes participate is missing. Protein
arginine methyltransferases (PRMTs), which methylate histones and are evolutionarily conserved from yeast to human,
constitute an example of chromatin modifying enzymes whose functional and regulatory networks remain unexplored. I
propose to use complementary state-of-the-art genomic and proteomic approaches in order to identify the protein networks
and cellular pathways that are linked to PRMTs. In parallel, I will identify novel regulatory circuits and define the molecular
mechanisms that control methylation of specific histone arginine residues. I will utilize the yeast S. cerevisiae as a model
organism because it allows genetic, biochemical and genomic approaches to be combined. Most importantly, many of the
pathways and mechanisms in yeast are highly conserved and therefore, the findings from this study will be pertinent to
human and other eukaryotic organisms. Establishing a global cellular wiring diagram of PRMTs will serve as a paradigm for
other chromatin modifiers and is imperative for assessing the efficacy of these enzymes as therapeutic targets.
Max ERC Funding
1 498 279 €
Duration
Start date: 2011-01-01, End date: 2016-06-30
Project acronym CleverGenes
Project Novel Gene Therapy Based on the Activation of Endogenous Genes for the Treatment of Ischemia - Concepts of endogenetherapy, release of promoter pausing, promoter-targeted ncRNAs and nuclear RNAi
Researcher (PI) Seppo Ylä-Herttuala
Host Institution (HI) ITA-SUOMEN YLIOPISTO
Call Details Advanced Grant (AdG), LS7, ERC-2014-ADG
Summary Background: Therapeutic angiogenesis with vascular endothelial growth factors (VEGFs) has great potential to become a novel, minimally invasive new treatment for a large number of patients with severe myocardial ischemia. However, this requires development of new technology. Advancing state-of-the-art: We propose a paradigm shift in gene therapy for chronic ischemia by activating endogenous VEGF-A,-B and -C genes and angiogenic transcription programs from the native promoters instead of gene transfer of exogenous cDNA to target tissues. We will develop a new platform technology (endogenetherapy) based on our novel concept of the release of promoter pausing and new promoter-targeted upregulating short hairpinRNAs, tissue-specific superenhancerRNAs activating specific transcription centers involving gene clusters in different chromosomal regions, small circularRNAs formed from self-splicing exons-introns that can be regulated with oligonucleotides and small molecules such as metabolites, nuclear RNAi vectors and specific CRISPR/gRNAmutatedCas9-VP16 technology with an ability to target integration into genomic safe harbor sites. After preclinical studies in mice and in a newly developed chronic cardiac ischemia model in pigs with special emphasis on the analysis of clinically relevant blood flow, metabolic and functional outcomes based on MRI, ultrasound, photoacoustic and PET imaging, the best construct will be taken to a phase I clinical study in patients with severe myocardial ischemia. Since endogenetherapy also involves epigenetic changes, which are reversible and long-lasting, we expect to efficiently activate natural angiogenic programs. Significance: If successful, this approach will begin a new era in gene therapy. Since there is a clear lack of technology capable of targeted upregulation of endogenous genes, the novel endogenetherapy approach may become widely applicable beyond cardiovascular diseases also in other areas of medicine and biomedical research.
Summary
Background: Therapeutic angiogenesis with vascular endothelial growth factors (VEGFs) has great potential to become a novel, minimally invasive new treatment for a large number of patients with severe myocardial ischemia. However, this requires development of new technology. Advancing state-of-the-art: We propose a paradigm shift in gene therapy for chronic ischemia by activating endogenous VEGF-A,-B and -C genes and angiogenic transcription programs from the native promoters instead of gene transfer of exogenous cDNA to target tissues. We will develop a new platform technology (endogenetherapy) based on our novel concept of the release of promoter pausing and new promoter-targeted upregulating short hairpinRNAs, tissue-specific superenhancerRNAs activating specific transcription centers involving gene clusters in different chromosomal regions, small circularRNAs formed from self-splicing exons-introns that can be regulated with oligonucleotides and small molecules such as metabolites, nuclear RNAi vectors and specific CRISPR/gRNAmutatedCas9-VP16 technology with an ability to target integration into genomic safe harbor sites. After preclinical studies in mice and in a newly developed chronic cardiac ischemia model in pigs with special emphasis on the analysis of clinically relevant blood flow, metabolic and functional outcomes based on MRI, ultrasound, photoacoustic and PET imaging, the best construct will be taken to a phase I clinical study in patients with severe myocardial ischemia. Since endogenetherapy also involves epigenetic changes, which are reversible and long-lasting, we expect to efficiently activate natural angiogenic programs. Significance: If successful, this approach will begin a new era in gene therapy. Since there is a clear lack of technology capable of targeted upregulation of endogenous genes, the novel endogenetherapy approach may become widely applicable beyond cardiovascular diseases also in other areas of medicine and biomedical research.
Max ERC Funding
2 437 500 €
Duration
Start date: 2015-11-01, End date: 2020-10-31
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 DIADRUG
Project Insulin resistance and diabetic nephropathy - development of novel in vivo models for drug discovery
Researcher (PI) Sanna Lehtonen
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), LS9, ERC-2009-StG
Summary Up to one third of diabetic patients develop nephropathy, a serious complication of diabetes. Microalbuminuria is the earliest sign of the complication, which may ultimately develop to end-stage renal disease requiring dialysis or a kidney transplant. Insulin resistance and metabolic syndrome are associated with an increased risk for diabetic nephropathy. Interestingly, glomerular epithelial cells or podocytes have recently been shown to be insulin responsive. Further, nephrin, a key structural component of podocytes, is essential for insulin action in these cells. Our novel findings show that adaptor protein CD2AP, an interaction partner of nephrin, associates with regulators of insulin signaling and glucose transport in glomeruli. The results suggest that nephrin and CD2AP are involved, by association with these proteins, in the regulation of insulin signaling and glucose transport in podocytes. We hypothesize that podocytes can develop insulin resistance and that disturbances in insulin response affect podocyte function and contribute to the development of diabetic nephropathy. The aim of this project is to clarify the mechanisms leading to development of insulin resistance in podocytes and to study the association between insulin resistance and the development of diabetic nephropathy. For this we will develop transgenic zebrafish and mouse models by overexpressing/knocking down insulin signaling-associated proteins specifically in podocytes. Further, we aim to identify novel drug leads to treat insulin resistance and diabetic nephropathy by performing high-throughput small molecule library screens on the developed transgenic fish models. The ultimate goal is to find a treatment to combat the early stages of diabetic nephropathy in humans.
Summary
Up to one third of diabetic patients develop nephropathy, a serious complication of diabetes. Microalbuminuria is the earliest sign of the complication, which may ultimately develop to end-stage renal disease requiring dialysis or a kidney transplant. Insulin resistance and metabolic syndrome are associated with an increased risk for diabetic nephropathy. Interestingly, glomerular epithelial cells or podocytes have recently been shown to be insulin responsive. Further, nephrin, a key structural component of podocytes, is essential for insulin action in these cells. Our novel findings show that adaptor protein CD2AP, an interaction partner of nephrin, associates with regulators of insulin signaling and glucose transport in glomeruli. The results suggest that nephrin and CD2AP are involved, by association with these proteins, in the regulation of insulin signaling and glucose transport in podocytes. We hypothesize that podocytes can develop insulin resistance and that disturbances in insulin response affect podocyte function and contribute to the development of diabetic nephropathy. The aim of this project is to clarify the mechanisms leading to development of insulin resistance in podocytes and to study the association between insulin resistance and the development of diabetic nephropathy. For this we will develop transgenic zebrafish and mouse models by overexpressing/knocking down insulin signaling-associated proteins specifically in podocytes. Further, we aim to identify novel drug leads to treat insulin resistance and diabetic nephropathy by performing high-throughput small molecule library screens on the developed transgenic fish models. The ultimate goal is to find a treatment to combat the early stages of diabetic nephropathy in humans.
Max ERC Funding
2 000 000 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym DOGPSYCH
Project Canine models of human psychiatric disease: identifying novel anxiety genes with the help of man's best friend
Researcher (PI) Hannes Tapani Lohi
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary Anxiety disorders include different forms of pathological fear and anxiety and rank among the most common health concerns in human medicine. Millions of people become affected every year, and many of them do not respond to treatments. Anxiety disorders are heritable, but genetically complex. As a result, traditional gene mapping methods in the human population with prominent locus and allelic heterogeneity have not succeeded. Similarly, rodents have provided some insights into the circuitry of anxiety, but naturally occurring versions do not exist and gene deletion studies have not provided adequate models. To break through and identify new anxiety genes, I propose a novel and unique approach that resorts to man s best friend, dog. Taking advantage of the exaggerated genetic homogeneity characteristic of purebred dogs, recent genomics tools and the existence of naturally occurring heritable behaviour disorders in dogs can remedy the current lack of a suitable animal model of human psychiatric disorders. I propose to collect and perform a genome-wide association study in four breed-specific anxiety traits in dogs representing the three major forms of human anxiety: compulsive pacing and tail-chasing, noise phobia, and shyness corresponding to human OCD, panic disorder and social phobia, respectively. Canine anxiety disorders respond to human medications and other phenomenological studies suggest a share biological mechanism in both species. The proposed research has the potential to discover new genetic risk factors, which eventually will shed light on the biological basis of common neuropsychiatric disorders in both dog and human, provide insight into etiological mechanisms, enable identification of individuals at high-risk for adverse health outcomes, and facilitate development of tailored treatments.
Summary
Anxiety disorders include different forms of pathological fear and anxiety and rank among the most common health concerns in human medicine. Millions of people become affected every year, and many of them do not respond to treatments. Anxiety disorders are heritable, but genetically complex. As a result, traditional gene mapping methods in the human population with prominent locus and allelic heterogeneity have not succeeded. Similarly, rodents have provided some insights into the circuitry of anxiety, but naturally occurring versions do not exist and gene deletion studies have not provided adequate models. To break through and identify new anxiety genes, I propose a novel and unique approach that resorts to man s best friend, dog. Taking advantage of the exaggerated genetic homogeneity characteristic of purebred dogs, recent genomics tools and the existence of naturally occurring heritable behaviour disorders in dogs can remedy the current lack of a suitable animal model of human psychiatric disorders. I propose to collect and perform a genome-wide association study in four breed-specific anxiety traits in dogs representing the three major forms of human anxiety: compulsive pacing and tail-chasing, noise phobia, and shyness corresponding to human OCD, panic disorder and social phobia, respectively. Canine anxiety disorders respond to human medications and other phenomenological studies suggest a share biological mechanism in both species. The proposed research has the potential to discover new genetic risk factors, which eventually will shed light on the biological basis of common neuropsychiatric disorders in both dog and human, provide insight into etiological mechanisms, enable identification of individuals at high-risk for adverse health outcomes, and facilitate development of tailored treatments.
Max ERC Funding
1 381 807 €
Duration
Start date: 2010-10-01, End date: 2015-09-30
Project acronym DrugComb
Project Informatics approaches for the rational selection of personalized cancer drug combinations
Researcher (PI) Jing TANG
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), LS7, ERC-2016-STG
Summary Making cancer treatment more personalized and effective is one of the grand challenges in our health care system. However, many drugs have entered clinical trials but so far showed limited efficacy or induced rapid development of resistance. We critically need multi-targeted drug combinations, which shall selectively inhibit the cancer cells and block the emergence of drug resistance. This project will develop mathematical and computational tools to identify drug combinations that can be used to provide personalized and more effective therapeutic strategies that may prevent acquired resistance. Utilizing molecular profiling and pharmacological screening data from patient-derived leukaemia and ovarian cancer samples, I will develop model-based clustering methods for identification of patient subgroups that are differentially responsive to first-line chemotherapy. For patients resistant to chemotherapy, I will develop network modelling approaches to predict the most potential drug combinations by understanding the underlying drug target interactions. The drug combination prediction will be made for each patient and will be validated using a preclinical drug testing platform on patient samples. I will explore the drug combination screen data to identify significant synergy at the therapeutically relevant doses. The drug combination hits will be mapped into signalling networks to infer their mechanisms. Drug combinations with selective efficacy in individual patient samples or in sample subgroups will be further translated into in treatment options by clinical collaborators. This will lead to novel and personalized strategies to treat cancer patients.
Summary
Making cancer treatment more personalized and effective is one of the grand challenges in our health care system. However, many drugs have entered clinical trials but so far showed limited efficacy or induced rapid development of resistance. We critically need multi-targeted drug combinations, which shall selectively inhibit the cancer cells and block the emergence of drug resistance. This project will develop mathematical and computational tools to identify drug combinations that can be used to provide personalized and more effective therapeutic strategies that may prevent acquired resistance. Utilizing molecular profiling and pharmacological screening data from patient-derived leukaemia and ovarian cancer samples, I will develop model-based clustering methods for identification of patient subgroups that are differentially responsive to first-line chemotherapy. For patients resistant to chemotherapy, I will develop network modelling approaches to predict the most potential drug combinations by understanding the underlying drug target interactions. The drug combination prediction will be made for each patient and will be validated using a preclinical drug testing platform on patient samples. I will explore the drug combination screen data to identify significant synergy at the therapeutically relevant doses. The drug combination hits will be mapped into signalling networks to infer their mechanisms. Drug combinations with selective efficacy in individual patient samples or in sample subgroups will be further translated into in treatment options by clinical collaborators. This will lead to novel and personalized strategies to treat cancer patients.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym DynaOmics
Project From longitudinal proteomics to dynamic individualized diagnostics
Researcher (PI) Laura Linnea Maria Elo-Uhlgren
Host Institution (HI) TURUN YLIOPISTO
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary Longitudinal omics data hold great promise to improve biomarker detection and enable dynamic individualized predictions. Recent technological advances have made proteomics an increasingly attractive option but clinical longitudinal proteomic datasets are still rare and computational tools for their analysis underdeveloped. The objective of this proposal is to create a roadmap to detect clinically feasible protein markers using longitudinal data and effective computational tools. A biomedical focus is on early detection of Type 1 diabetes (T1D). Specific objectives are:
1) Novel biomarker detector using longitudinal data. DynaOmics introduces novel types of multi-level dynamic markers that are undetectable in conventional single-time cross-sectional studies (e.g. within-individual changes in abundance or associations), develops optimization methods for their robust and reproducible detection within and across individuals, and validates their utility in well-defined samples.
2) Individualized disease risk prediction dynamically. DynaOmics develops dynamic individualized predictive models using the multi-level longitudinal proteome features and novel statistical and machine learning methods that have previously not been used in this context, including joint models of longitudinal and time-to-event data, and one-class classification type techniques.
3) Dynamic prediction of T1D. DynaOmics builds a predictive model of dynamic T1D risk to assist early detection of the disease, which is crucial for developing future therapeutic and preventive strategies. T1D typically involves a relatively long symptom-free period before clinical diagnosis but current tools to predict early T1D risk have restricted power.
The objectives involve innovative and unconventional approaches and address major unmet challenges in the field, having high potential to open new avenues for diagnosis and treatment of complex diseases and fundamentally novel insights towards precision medicine.
Summary
Longitudinal omics data hold great promise to improve biomarker detection and enable dynamic individualized predictions. Recent technological advances have made proteomics an increasingly attractive option but clinical longitudinal proteomic datasets are still rare and computational tools for their analysis underdeveloped. The objective of this proposal is to create a roadmap to detect clinically feasible protein markers using longitudinal data and effective computational tools. A biomedical focus is on early detection of Type 1 diabetes (T1D). Specific objectives are:
1) Novel biomarker detector using longitudinal data. DynaOmics introduces novel types of multi-level dynamic markers that are undetectable in conventional single-time cross-sectional studies (e.g. within-individual changes in abundance or associations), develops optimization methods for their robust and reproducible detection within and across individuals, and validates their utility in well-defined samples.
2) Individualized disease risk prediction dynamically. DynaOmics develops dynamic individualized predictive models using the multi-level longitudinal proteome features and novel statistical and machine learning methods that have previously not been used in this context, including joint models of longitudinal and time-to-event data, and one-class classification type techniques.
3) Dynamic prediction of T1D. DynaOmics builds a predictive model of dynamic T1D risk to assist early detection of the disease, which is crucial for developing future therapeutic and preventive strategies. T1D typically involves a relatively long symptom-free period before clinical diagnosis but current tools to predict early T1D risk have restricted power.
The objectives involve innovative and unconventional approaches and address major unmet challenges in the field, having high potential to open new avenues for diagnosis and treatment of complex diseases and fundamentally novel insights towards precision medicine.
Max ERC Funding
1 499 869 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym Elephant Project
Project How elephants grow old
Researcher (PI) Virpi Annikki Lummaa
Host Institution (HI) TURUN YLIOPISTO
Call Details Consolidator Grant (CoG), LS8, ERC-2014-CoG
Summary The ageing population structure of most European countries has major health, economic and social consequences that lead to a need to better understand both the evolutionary limitations of deferring ageing, as well as the mechanisms involved in growing old. Ageing involves reduced fertility, mobility and ability to combat disease, but some individuals cope with growing old better than others. Improving the quality of life at old age and predicting future changes in longevity patterns of societies might depend on our ability to develop indicators of how old we really are and how many healthy years we have ahead, and how those indicators depend on our health history across several decades. Yet, most model species used in biology are short-lived and provide a poor comparison to long-lived mammals such as humans. Further, they do not often inform on the mechanisms of ageing alongside its fitness consequences in natural populations of long-lived mammals. This project integrates different ageing mechanisms with unique data on lifelong disease and reproductive history in the most long-lived non-human mammal studied so far, the Asian elephant. I will examine how different mechanisms of ageing (telomere dynamics, oxidative stress and telomerase activity) interact with lifelong disease and reproductive history, and current endocrinological measures of stress and reproductive status. This will help us to better understand both the mechanisms of ageing and their consequences on senescence rates. To do so, I will combine the most comprehensive demographic data (N~10.000) on Asian elephants in the world with bi-monthly health assessments and disease records across life (N~2500) and with longitudinal markers of ageing and hormonal correlates of stress and reproductive potential (N~240). Understanding changes in health across life and its links to ageing rates, stress levels and life-history in a species as long-lived as humans will be relevant to a large range of end-users.
Summary
The ageing population structure of most European countries has major health, economic and social consequences that lead to a need to better understand both the evolutionary limitations of deferring ageing, as well as the mechanisms involved in growing old. Ageing involves reduced fertility, mobility and ability to combat disease, but some individuals cope with growing old better than others. Improving the quality of life at old age and predicting future changes in longevity patterns of societies might depend on our ability to develop indicators of how old we really are and how many healthy years we have ahead, and how those indicators depend on our health history across several decades. Yet, most model species used in biology are short-lived and provide a poor comparison to long-lived mammals such as humans. Further, they do not often inform on the mechanisms of ageing alongside its fitness consequences in natural populations of long-lived mammals. This project integrates different ageing mechanisms with unique data on lifelong disease and reproductive history in the most long-lived non-human mammal studied so far, the Asian elephant. I will examine how different mechanisms of ageing (telomere dynamics, oxidative stress and telomerase activity) interact with lifelong disease and reproductive history, and current endocrinological measures of stress and reproductive status. This will help us to better understand both the mechanisms of ageing and their consequences on senescence rates. To do so, I will combine the most comprehensive demographic data (N~10.000) on Asian elephants in the world with bi-monthly health assessments and disease records across life (N~2500) and with longitudinal markers of ageing and hormonal correlates of stress and reproductive potential (N~240). Understanding changes in health across life and its links to ageing rates, stress levels and life-history in a species as long-lived as humans will be relevant to a large range of end-users.
Max ERC Funding
1 949 316 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
