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 GEDA
Project Global Environmental Decision Analysis
Researcher (PI) Atte Jaakko Moilanen
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), LS8, ERC-2010-StG_20091118
Summary Habitat degradation and climate change are generally considered the greatest threats to biodiversity globally. Together, these processes pose an urgent challenge to conservation science, requiring ever increasing efficiency in ecologically-based decision making, to slow down, and hopefully eventually reverse, the ongoing global loss of biodiversity. In responding to this challenge, I am proposing a project in which the over-arching goal is to provide improved conservation-oriented analytical methods and tools to underpin knowledge-based land-use planning and associated political decision making. The proposed work builds on a broad established history of research in the field of spatial ecology and conservation prioritization.
Specific components of the proposal include: (i) developing the general conceptual, ecological, methodological and statistical basis of environmental and conservation resource allocation: (ii) combining species and community-level prioritization approaches for data-poor areas of the world; (iii) developing methods for alleviating the negative ecological consequences of climate change, based on connectivity both in geographic and environmental space; (iv) developing an uncertainty-analytic method for the planning of habitat restoration and calculation of compensation ratios for habitat that will be impacted due to economic activity, (v) developing methods for allocating alternative conservation actions (protection, maintenance, restoration) in combination with habitat-specific loss rates in spatial conservation prioritization, and (vi) implementing the proposed methods as publicly available, efficient and well-documented software packages. Particular emphasis will be placed on solving the algorithmic challenges involved in analyzing the large data sets that are becoming increasingly available as the distributions of environmental conditions and biodiversity features are derived from large-scale high-resolution remote-sensing data.
Summary
Habitat degradation and climate change are generally considered the greatest threats to biodiversity globally. Together, these processes pose an urgent challenge to conservation science, requiring ever increasing efficiency in ecologically-based decision making, to slow down, and hopefully eventually reverse, the ongoing global loss of biodiversity. In responding to this challenge, I am proposing a project in which the over-arching goal is to provide improved conservation-oriented analytical methods and tools to underpin knowledge-based land-use planning and associated political decision making. The proposed work builds on a broad established history of research in the field of spatial ecology and conservation prioritization.
Specific components of the proposal include: (i) developing the general conceptual, ecological, methodological and statistical basis of environmental and conservation resource allocation: (ii) combining species and community-level prioritization approaches for data-poor areas of the world; (iii) developing methods for alleviating the negative ecological consequences of climate change, based on connectivity both in geographic and environmental space; (iv) developing an uncertainty-analytic method for the planning of habitat restoration and calculation of compensation ratios for habitat that will be impacted due to economic activity, (v) developing methods for allocating alternative conservation actions (protection, maintenance, restoration) in combination with habitat-specific loss rates in spatial conservation prioritization, and (vi) implementing the proposed methods as publicly available, efficient and well-documented software packages. Particular emphasis will be placed on solving the algorithmic challenges involved in analyzing the large data sets that are becoming increasingly available as the distributions of environmental conditions and biodiversity features are derived from large-scale high-resolution remote-sensing data.
Max ERC Funding
1 495 213 €
Duration
Start date: 2011-01-01, End date: 2015-12-31
Project acronym METABOMIT
Project Metabolic consequences of mitochondrial dysfunction
Researcher (PI) Anu Elina Wartiovaara
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Advanced Grant (AdG), LS4, ERC-2010-AdG_20100317
Summary This proposal aims to clarify mitochondrial contribution to obesity and thinness, using carefully characterized mitochondrial disease and obese patient materials, and genetically modified disease models. Manifestations of mitochondrial respiratory chain (RC) defects range from infantile multisystem disorders to adult-onset myopathies or neurodegeneration, and even aging-related wasting. Why defects in oxidative ATP production can lead to such variety of manifestations and tissue specificity is unknown. We have previously identified a number of gene defects that lead to RC disorders. In addition to neurological symptoms, these patients often show various metabolic manifestations: specific gene defects associate with short stature and thinness, whereas others with metabolic syndrome or obesity. This implies that specific mitochondrial defects can have opposing effects for fat storage or utilization. The involved pathways may contribute to mitochondrial disease progression, but are unknown.
We propose to a) undertake a major clinical study on genetically defined, obese or thin, mitochondrial patients, and examine their metabolic phenotype in finest detail. These data will be compared to those from normal obesity, to search for common mechanisms between mitochondrial and general obesity. b) generate a set of disease models for mitochondrial disorders associated with obesity, and knock-out models for specific signallers for crossing with the disease models. c) identify in detail the involved regulatory pathways, and utilize these for searching chemical compounds that could modulate the response, and have therapeutic potential. The project has potential for major breakthroughs in the fields of mitochondrial disease pathogenesis and treatment, neurodegeneration and obesity.
Summary
This proposal aims to clarify mitochondrial contribution to obesity and thinness, using carefully characterized mitochondrial disease and obese patient materials, and genetically modified disease models. Manifestations of mitochondrial respiratory chain (RC) defects range from infantile multisystem disorders to adult-onset myopathies or neurodegeneration, and even aging-related wasting. Why defects in oxidative ATP production can lead to such variety of manifestations and tissue specificity is unknown. We have previously identified a number of gene defects that lead to RC disorders. In addition to neurological symptoms, these patients often show various metabolic manifestations: specific gene defects associate with short stature and thinness, whereas others with metabolic syndrome or obesity. This implies that specific mitochondrial defects can have opposing effects for fat storage or utilization. The involved pathways may contribute to mitochondrial disease progression, but are unknown.
We propose to a) undertake a major clinical study on genetically defined, obese or thin, mitochondrial patients, and examine their metabolic phenotype in finest detail. These data will be compared to those from normal obesity, to search for common mechanisms between mitochondrial and general obesity. b) generate a set of disease models for mitochondrial disorders associated with obesity, and knock-out models for specific signallers for crossing with the disease models. c) identify in detail the involved regulatory pathways, and utilize these for searching chemical compounds that could modulate the response, and have therapeutic potential. The project has potential for major breakthroughs in the fields of mitochondrial disease pathogenesis and treatment, neurodegeneration and obesity.
Max ERC Funding
2 500 000 €
Duration
Start date: 2011-06-01, End date: 2016-05-31
Project acronym MOCAPAF
Project Role of Molecular Clusters in Atmospheric Particle Formation
Researcher (PI) Hanna Vehkamäki
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), PE4, ERC-2010-StG_20091028
Summary Climate change is currently one of the central scientific issues in the world, and the ability to reliably forecast climate is crucial for making political decisions that affect the lives of billions of people. Aerosols remain the dominant uncertainty in predicting radiative forcing and future climate change, and also have adverse effects on human health and visibility. One of the least-well understood aerosol-related processes is nucleation: the formation of new particles from condensable vapours. While nucleation is related primarily to neutral clusters, state-of-the-art experimental methods measure only charged clusters.
The main scientific objectives of this project are 1) to understand the chemical composition of charged and especially neutral atmospheric clusters from molecular to multi-nanometre scale, and explain the mechanism by which they nucleate, and 2) to direct current intense instrument development and provide theoretical tools to maximize the information on neutral clusters that can be obtained from experimental results on charged clusters.
Our scientific plan consists of a multilevel computational effort to provide formation rates and properties of atmospheric clusters and particles to aerosol dynamic and climate modellers. To capture the properties of the smallest clusters, we need to perform quantum chemical calculations, combined with simulations on cluster formation kinetics. Unfortunately, these methods are computationally far too demanding to describe the entire nucleation process. Thus, we will feed quantum chemical results to classical thermodynamic models, the results of which in turn must be parameterized for efficient use in larger-scale models.
Summary
Climate change is currently one of the central scientific issues in the world, and the ability to reliably forecast climate is crucial for making political decisions that affect the lives of billions of people. Aerosols remain the dominant uncertainty in predicting radiative forcing and future climate change, and also have adverse effects on human health and visibility. One of the least-well understood aerosol-related processes is nucleation: the formation of new particles from condensable vapours. While nucleation is related primarily to neutral clusters, state-of-the-art experimental methods measure only charged clusters.
The main scientific objectives of this project are 1) to understand the chemical composition of charged and especially neutral atmospheric clusters from molecular to multi-nanometre scale, and explain the mechanism by which they nucleate, and 2) to direct current intense instrument development and provide theoretical tools to maximize the information on neutral clusters that can be obtained from experimental results on charged clusters.
Our scientific plan consists of a multilevel computational effort to provide formation rates and properties of atmospheric clusters and particles to aerosol dynamic and climate modellers. To capture the properties of the smallest clusters, we need to perform quantum chemical calculations, combined with simulations on cluster formation kinetics. Unfortunately, these methods are computationally far too demanding to describe the entire nucleation process. Thus, we will feed quantum chemical results to classical thermodynamic models, the results of which in turn must be parameterized for efficient use in larger-scale models.
Max ERC Funding
1 476 418 €
Duration
Start date: 2011-02-01, End date: 2016-01-31
Project acronym NGG
Project Next Generation Genetics of Cancer Predisposition
Researcher (PI) Lauri Aaltonen
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Advanced Grant (AdG), LS7, ERC-2010-AdG_20100317
Summary Unravelling genetic components of human tumor predisposition has contributed significantly to our understanding on molecular basis of cancer, and cancer prevention in the context of hereditary tumor susceptibility is one of the early examples of benefits from genetic disease information. Research into cancer susceptibility is of great importance, and as shown in this proposal Finland provides unique interdisciplinary possibilities to take the field forward. Indeed, in the near future ability to recruit very small groups of patients with a potentially novel cancer susceptibility phenotype will be more relevant than ever. Such materials have been resistant to previous gene identification approaches but lend themselves towards success by exomic and whole genome sequencing.
Important discoveries are anticipated in the following fields of research to be conducted under NGG:
1) Identification of rare high-penetrance Mendelian cancer predisposition conditions, and the respective susceptibility genes. One should note that the impact of a gene discovery for basic understanding of key cellular processes is not related to the frequency of the predisposition condition (e.g. RB, LKB1, P53 etc).
2) Identification of moderate penetrance cancer susceptibility genes. Such phenotypes have been difficult to approach with traditional gene identification methods because large pedigrees with multiple affected individuals and few or no phenocopies are not easily identified. Also, the current GWAS approaches are not ideal to detect these loci due to relative rarity of the responsible variants.
3) Characterization of common variants associated with cancer susceptibility.
Summary
Unravelling genetic components of human tumor predisposition has contributed significantly to our understanding on molecular basis of cancer, and cancer prevention in the context of hereditary tumor susceptibility is one of the early examples of benefits from genetic disease information. Research into cancer susceptibility is of great importance, and as shown in this proposal Finland provides unique interdisciplinary possibilities to take the field forward. Indeed, in the near future ability to recruit very small groups of patients with a potentially novel cancer susceptibility phenotype will be more relevant than ever. Such materials have been resistant to previous gene identification approaches but lend themselves towards success by exomic and whole genome sequencing.
Important discoveries are anticipated in the following fields of research to be conducted under NGG:
1) Identification of rare high-penetrance Mendelian cancer predisposition conditions, and the respective susceptibility genes. One should note that the impact of a gene discovery for basic understanding of key cellular processes is not related to the frequency of the predisposition condition (e.g. RB, LKB1, P53 etc).
2) Identification of moderate penetrance cancer susceptibility genes. Such phenotypes have been difficult to approach with traditional gene identification methods because large pedigrees with multiple affected individuals and few or no phenocopies are not easily identified. Also, the current GWAS approaches are not ideal to detect these loci due to relative rarity of the responsible variants.
3) Characterization of common variants associated with cancer susceptibility.
Max ERC Funding
2 483 525 €
Duration
Start date: 2011-06-01, End date: 2016-05-31
Project acronym TX-FACTORS
Project NEW BIOLOGICAL FUNCTIONS AND THERAPEUTIC POTENTIAL OF
VASCULAR ENDOTHELIAL GROWTH FACTORS
Researcher (PI) Kari Kustaa Alitalo
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Advanced Grant (AdG), LS7, ERC-2010-AdG_20100317
Summary This application promises to provide new treatment options for cancer and cardiovascular diseases that are the leading causes of morbidity and mortality in the western world. Current cardiovascular and cancer therapies are often insufficient, unsuccessful or not suitable for all patients. Inhibition of angiogenesis is already used in the clinics, but with limited success. On the other hand, stimulation of the growth of blood vessels, angiogenesis, and of arteriogenesis, the growth of (collateral) arteries, has been unsuccessfully tried for the treatment of tissue ischemia. The aim of this research plan is to reveal new disease-related functions of endothelial growth factors and their signal transduction in cancer and cardiovascular disease and to establish preclinical models of effective therapy based on new knowledge of the biology of vascular endothelial growth factors (VEGFs), angiopoietins (Ang), angiogenesis and lymphangiogenesis. We will embark on new studies based on our novel discoveries on the crosstalk between endothelial growth factor pathways in tumor angiogenesis, the involvement of lymphatic vessels in the development of obesity and associated inflammation, and on the striking effects of VEGF-B on cardiac muscle and vessels. We will develop molecular genetic and iPS cell derived models, and use functional genomics, proteomics and metabolomics, viral gene delivery and blocking reagents from human antibody libraries for our studies that should be of high priority in basic science and medicine. My laboratory is uniquely suited and networked for new discoveries to advance therapies for both cancer and cardiovascular diseases. Some of our work has already been translated to clinical development and we aim to provide additional drug candidates in this project.
Summary
This application promises to provide new treatment options for cancer and cardiovascular diseases that are the leading causes of morbidity and mortality in the western world. Current cardiovascular and cancer therapies are often insufficient, unsuccessful or not suitable for all patients. Inhibition of angiogenesis is already used in the clinics, but with limited success. On the other hand, stimulation of the growth of blood vessels, angiogenesis, and of arteriogenesis, the growth of (collateral) arteries, has been unsuccessfully tried for the treatment of tissue ischemia. The aim of this research plan is to reveal new disease-related functions of endothelial growth factors and their signal transduction in cancer and cardiovascular disease and to establish preclinical models of effective therapy based on new knowledge of the biology of vascular endothelial growth factors (VEGFs), angiopoietins (Ang), angiogenesis and lymphangiogenesis. We will embark on new studies based on our novel discoveries on the crosstalk between endothelial growth factor pathways in tumor angiogenesis, the involvement of lymphatic vessels in the development of obesity and associated inflammation, and on the striking effects of VEGF-B on cardiac muscle and vessels. We will develop molecular genetic and iPS cell derived models, and use functional genomics, proteomics and metabolomics, viral gene delivery and blocking reagents from human antibody libraries for our studies that should be of high priority in basic science and medicine. My laboratory is uniquely suited and networked for new discoveries to advance therapies for both cancer and cardiovascular diseases. Some of our work has already been translated to clinical development and we aim to provide additional drug candidates in this project.
Max ERC Funding
2 499 884 €
Duration
Start date: 2011-06-01, End date: 2016-05-31
