Project acronym Age Asymmetry
Project Age-Selective Segregation of Organelles
Researcher (PI) Pekka Aleksi Katajisto
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), LS3, ERC-2015-STG
Summary Our tissues are constantly renewed by stem cells. Over time, stem cells accumulate cellular damage that will compromise renewal and results in aging. As stem cells can divide asymmetrically, segregation of harmful factors to the differentiating daughter cell could be one possible mechanism for slowing damage accumulation in the stem cell. However, current evidence for such mechanisms comes mainly from analogous findings in yeast, and studies have concentrated only on few types of cellular damage.
I hypothesize that the chronological age of a subcellular component is a proxy for all the damage it has sustained. In order to secure regeneration, mammalian stem cells may therefore specifically sort old cellular material asymmetrically. To study this, I have developed a novel strategy and tools to address the age-selective segregation of any protein in stem cell division. Using this approach, I have already discovered that stem-like cells of the human mammary epithelium indeed apportion chronologically old mitochondria asymmetrically in cell division, and enrich old mitochondria to the differentiating daughter cell. We will investigate the mechanisms underlying this novel phenomenon, and its relevance for mammalian aging.
We will first identify how old and young mitochondria differ, and how stem cells recognize them to facilitate the asymmetric segregation. Next, we will analyze the extent of asymmetric age-selective segregation by targeting several other subcellular compartments in a stem cell division. Finally, we will determine whether the discovered age-selective segregation is a general property of stem cell in vivo, and it's functional relevance for maintenance of stem cells and tissue regeneration. Our discoveries may open new possibilities to target aging associated functional decline by induction of asymmetric age-selective organelle segregation.
Summary
Our tissues are constantly renewed by stem cells. Over time, stem cells accumulate cellular damage that will compromise renewal and results in aging. As stem cells can divide asymmetrically, segregation of harmful factors to the differentiating daughter cell could be one possible mechanism for slowing damage accumulation in the stem cell. However, current evidence for such mechanisms comes mainly from analogous findings in yeast, and studies have concentrated only on few types of cellular damage.
I hypothesize that the chronological age of a subcellular component is a proxy for all the damage it has sustained. In order to secure regeneration, mammalian stem cells may therefore specifically sort old cellular material asymmetrically. To study this, I have developed a novel strategy and tools to address the age-selective segregation of any protein in stem cell division. Using this approach, I have already discovered that stem-like cells of the human mammary epithelium indeed apportion chronologically old mitochondria asymmetrically in cell division, and enrich old mitochondria to the differentiating daughter cell. We will investigate the mechanisms underlying this novel phenomenon, and its relevance for mammalian aging.
We will first identify how old and young mitochondria differ, and how stem cells recognize them to facilitate the asymmetric segregation. Next, we will analyze the extent of asymmetric age-selective segregation by targeting several other subcellular compartments in a stem cell division. Finally, we will determine whether the discovered age-selective segregation is a general property of stem cell in vivo, and it's functional relevance for maintenance of stem cells and tissue regeneration. Our discoveries may open new possibilities to target aging associated functional decline by induction of asymmetric age-selective organelle segregation.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
Project acronym BRAIN2BRAIN
Project Towards two-person neuroscience
Researcher (PI) Riitta Kyllikki Hari
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary Humans interact with other people throughout their lives. This project aims to demonstrate that the complex social shaping of the human brain can be adequately tackled only by taking a leap from the conven-tional single-person neuroscience to two-person neuroscience. We will (1) develop a conceptual framework and experimental setups for two-person neuroscience, (2) apply time-sensitive methods for studies of two interacting persons, monitoring both brain and autonomic nervous activity to also cover the brain body connection, (3) use gaze as an index of subject s attention to simplify signal analysis in natural environments, and (4) apply insights from two-person neuroscience into disorders of social interaction. Brain activity will be recorded with millisecond-accurate whole-scalp (306-channel) magnetoencepha-lography (MEG), associated with EEG, and with the millimeter-accurate 3-tesla functional magnetic reso-nance imaging (fMRI). Heart rate, respiration, galvanic skin response, and pupil diameter inform about body function. A new psychophysiological interaction setting will be built, comprising a two-person eye-tracking system. Novel analysis methods will be developed to follow the interaction and possible synchronization of the two persons signals. This uncoventional approach crosses borders of neuroscience, social psychology, psychophysiology, psychiatry, medical imaging, and signal analysis, with intriguing connections to old philosophical questions, such as intersubjectivity and emphatic attunement. The results could open an unprecedented window into human human, instead of just brain brain, interactions, helping to understand also social disorders, such as autism and schizophrenia. Further applications include master apprentice and patient therapist relationships. Advancing from studies of single persons towards two-person neuroscience shows promise of a break-through in understanding the dynamic social shaping of human brain and mind.
Summary
Humans interact with other people throughout their lives. This project aims to demonstrate that the complex social shaping of the human brain can be adequately tackled only by taking a leap from the conven-tional single-person neuroscience to two-person neuroscience. We will (1) develop a conceptual framework and experimental setups for two-person neuroscience, (2) apply time-sensitive methods for studies of two interacting persons, monitoring both brain and autonomic nervous activity to also cover the brain body connection, (3) use gaze as an index of subject s attention to simplify signal analysis in natural environments, and (4) apply insights from two-person neuroscience into disorders of social interaction. Brain activity will be recorded with millisecond-accurate whole-scalp (306-channel) magnetoencepha-lography (MEG), associated with EEG, and with the millimeter-accurate 3-tesla functional magnetic reso-nance imaging (fMRI). Heart rate, respiration, galvanic skin response, and pupil diameter inform about body function. A new psychophysiological interaction setting will be built, comprising a two-person eye-tracking system. Novel analysis methods will be developed to follow the interaction and possible synchronization of the two persons signals. This uncoventional approach crosses borders of neuroscience, social psychology, psychophysiology, psychiatry, medical imaging, and signal analysis, with intriguing connections to old philosophical questions, such as intersubjectivity and emphatic attunement. The results could open an unprecedented window into human human, instead of just brain brain, interactions, helping to understand also social disorders, such as autism and schizophrenia. Further applications include master apprentice and patient therapist relationships. Advancing from studies of single persons towards two-person neuroscience shows promise of a break-through in understanding the dynamic social shaping of human brain and mind.
Max ERC Funding
2 489 643 €
Duration
Start date: 2009-01-01, End date: 2014-12-31
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 EPISUSCEPTIBILITY
Project Epigenome and Cancer Susceptibility
Researcher (PI) Päivi Tuulikki Peltomäki
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Advanced Grant (AdG), LS7, ERC-2008-AdG
Summary Early detection is crucial for the outcome of most cancers. Prevention of cancer development is even more desirable. To facilitate these ultimate goals we aim to construct a comprehensive view of the stepwise process through which common human cancers, such as colorectal cancer, arise. In particular, we aim to identify novel mechanisms of cancer susceptibility by focusing on the epigenome, whose alterations may underlie several phenomena related to chronic adult-onset disease that are not explained by genetics alone. The stepwise process of carcinogenesis can be accelerated or halted for various reasons, including inherited susceptibility and diet. The human multi-organ cancer syndromes hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) as well as their murine counterparts, the Mlh1+/- mouse and the ApcMin/+ mouse, will be used as shortcuts to study the interplay between the epigenome and genome in tumorigenesis and to identify biomarkers of cancer susceptibility, malignant transformation, and tumor progression. This will be achieved by molecular profiling of normal and tumor tissues, cell line studies, in vitro functional assays, and in silico approaches. Additionally, the role that the epigenome plays to mediate the effects of the Western type diet on colorectal tumorigenesis will be examined in the mouse. Unlike genetic changes, epigenetic alterations are potentially reversible, which makes them promising targets for preventive and therapeutic interventions.
Summary
Early detection is crucial for the outcome of most cancers. Prevention of cancer development is even more desirable. To facilitate these ultimate goals we aim to construct a comprehensive view of the stepwise process through which common human cancers, such as colorectal cancer, arise. In particular, we aim to identify novel mechanisms of cancer susceptibility by focusing on the epigenome, whose alterations may underlie several phenomena related to chronic adult-onset disease that are not explained by genetics alone. The stepwise process of carcinogenesis can be accelerated or halted for various reasons, including inherited susceptibility and diet. The human multi-organ cancer syndromes hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) as well as their murine counterparts, the Mlh1+/- mouse and the ApcMin/+ mouse, will be used as shortcuts to study the interplay between the epigenome and genome in tumorigenesis and to identify biomarkers of cancer susceptibility, malignant transformation, and tumor progression. This will be achieved by molecular profiling of normal and tumor tissues, cell line studies, in vitro functional assays, and in silico approaches. Additionally, the role that the epigenome plays to mediate the effects of the Western type diet on colorectal tumorigenesis will be examined in the mouse. Unlike genetic changes, epigenetic alterations are potentially reversible, which makes them promising targets for preventive and therapeutic interventions.
Max ERC Funding
2 500 000 €
Duration
Start date: 2009-04-01, End date: 2014-09-30
Project acronym HRMEG
Project HRMEG: High-resolution magnetoencephalography: Towards non-invasive corticography
Researcher (PI) Lauri Tapio Parkkonen
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary To date, neuroimaging has provided a wealth of information on how the human brain works in health and disease. With functional magnetic resonance imaging (fMRI), we can obtain spatially precise information about long-lasting brain activations whereas electro- and magnetoencephalography (EEG/MEG) can track transient cortical responses at millisecond resolution. However, none of these methods excel in time-resolved detection of sustained cortical activations, which are typically reflected as bursts of gamma-range (30–150 Hz) oscillations, frequently present in invasive recordings in patients. Although we have recently demonstrated that in exceptional situations MEG can detect even single gamma responses, their signal-to-noise ratio is usually prohibitively low, largely due to the substantial distance (4–5 cm) between cortex and sensors. Here, I propose to exploit recent advances in a novel magnetic sensor technology—atomic magnetometry—to construct a new kind of MEG system that allows capturing cerebral magnetic fields within millimetres from the scalp. Our simulations show that this proximity leads up to a 5-fold increase in the signal amplitude and an order-of-magnitude improvement of spatial resolution compared to conventional MEG. Therefore, a high-resolution MEG (HRMEG) system based on atomic magnetometers should enable non-invasive recordings of cortical activity at unprecedented sensitivity and detail level, which I propose to capitalize on by characterizing cortical responses, particularly gamma oscillations, during complex cognitive tasks. Additionally, since atomic magnetometers can recover within milliseconds from fields of several tesla, I also propose to combine transcranial magnetic stimulation (TMS) with MEG, leveraging the reciprocity of TMS and MEG and thus allowing better-than-ever characterization of TMS-evoked responses. This proposal comprises the research towards a HRMEG system and its application to study the working human brain in a new way.
Summary
To date, neuroimaging has provided a wealth of information on how the human brain works in health and disease. With functional magnetic resonance imaging (fMRI), we can obtain spatially precise information about long-lasting brain activations whereas electro- and magnetoencephalography (EEG/MEG) can track transient cortical responses at millisecond resolution. However, none of these methods excel in time-resolved detection of sustained cortical activations, which are typically reflected as bursts of gamma-range (30–150 Hz) oscillations, frequently present in invasive recordings in patients. Although we have recently demonstrated that in exceptional situations MEG can detect even single gamma responses, their signal-to-noise ratio is usually prohibitively low, largely due to the substantial distance (4–5 cm) between cortex and sensors. Here, I propose to exploit recent advances in a novel magnetic sensor technology—atomic magnetometry—to construct a new kind of MEG system that allows capturing cerebral magnetic fields within millimetres from the scalp. Our simulations show that this proximity leads up to a 5-fold increase in the signal amplitude and an order-of-magnitude improvement of spatial resolution compared to conventional MEG. Therefore, a high-resolution MEG (HRMEG) system based on atomic magnetometers should enable non-invasive recordings of cortical activity at unprecedented sensitivity and detail level, which I propose to capitalize on by characterizing cortical responses, particularly gamma oscillations, during complex cognitive tasks. Additionally, since atomic magnetometers can recover within milliseconds from fields of several tesla, I also propose to combine transcranial magnetic stimulation (TMS) with MEG, leveraging the reciprocity of TMS and MEG and thus allowing better-than-ever characterization of TMS-evoked responses. This proposal comprises the research towards a HRMEG system and its application to study the working human brain in a new way.
Max ERC Funding
1 498 806 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym MITO BY-PASS
Project Molecular by-pass therapy for mitochondrial dysfunction
Researcher (PI) Howard Trevor Jacobs
Host Institution (HI) TAMPEREEN YLIOPISTO
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary Many eukaryotes, but not the higher metazoans such as vertebrates or arthropods, possess intrinsic by-pass systems that provide alternative routes for electron flow from NADH to oxygen. Whereas the standard mitochondrial OXPHOS system couples electron transport to proton pumping across the inner mitochondrial membrane, creating the proton gradient which is used to drive ATP synthesis and other energy-requiring processes, the by-pass enzymes are non-proton-pumping, and their activity is redox-regulated rather than subject to ATP requirements. My laboratory has engineered two of these by-pass enzymes, the single-subunit NADH dehydrogenase Ndi1p from yeast, and the alternative oxidase AOX from Ciona intestinalis, for expression in Drosophila and mammalian cells. Their expression is benign, and the enzymes appear to be almost inert, except under conditions of redox stress induced by OXPHOS toxins or mutations. The research set out in this proposal will explore the utility of these by-passes for alleviating metabolic stress in the whole organism and in specific tissues, arising from mitochondrial OXPHOS dysfunction. Specifically, I will test the ability of Ndi1p and AOX in Drosophila and in mammalian models to compensate for the toxicity of OXPHOS poisons, to complement disease-equivalent mutations impairing the assembly or function of the OXPHOS system, and to diminish the pathological excess production of reactive oxygen species seen in many neurodegenerative disorders associated with OXPHOS impairment, and under conditions of ischemia-reperfusion. The attenuation of endogenous mitochondrial ROS production by deployment of these by-pass enzymes also offers a novel route to testing the mitochondrial (oxyradical) theory of ageing.
Summary
Many eukaryotes, but not the higher metazoans such as vertebrates or arthropods, possess intrinsic by-pass systems that provide alternative routes for electron flow from NADH to oxygen. Whereas the standard mitochondrial OXPHOS system couples electron transport to proton pumping across the inner mitochondrial membrane, creating the proton gradient which is used to drive ATP synthesis and other energy-requiring processes, the by-pass enzymes are non-proton-pumping, and their activity is redox-regulated rather than subject to ATP requirements. My laboratory has engineered two of these by-pass enzymes, the single-subunit NADH dehydrogenase Ndi1p from yeast, and the alternative oxidase AOX from Ciona intestinalis, for expression in Drosophila and mammalian cells. Their expression is benign, and the enzymes appear to be almost inert, except under conditions of redox stress induced by OXPHOS toxins or mutations. The research set out in this proposal will explore the utility of these by-passes for alleviating metabolic stress in the whole organism and in specific tissues, arising from mitochondrial OXPHOS dysfunction. Specifically, I will test the ability of Ndi1p and AOX in Drosophila and in mammalian models to compensate for the toxicity of OXPHOS poisons, to complement disease-equivalent mutations impairing the assembly or function of the OXPHOS system, and to diminish the pathological excess production of reactive oxygen species seen in many neurodegenerative disorders associated with OXPHOS impairment, and under conditions of ischemia-reperfusion. The attenuation of endogenous mitochondrial ROS production by deployment of these by-pass enzymes also offers a novel route to testing the mitochondrial (oxyradical) theory of ageing.
Max ERC Funding
2 436 000 €
Duration
Start date: 2009-04-01, End date: 2015-03-31
Project acronym MYCLASS
Project Towards prevention, early diagnosis, and noninvasive treatment of uterine leiomyomas through molecular classification
Researcher (PI) Lauri Aaltonen
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Advanced Grant (AdG), LS7, ERC-2015-AdG
Summary Every fourth woman suffers from uterine leiomyomas (ULs) – benign tumors of the uterine smooth muscle wall - at some point in premenopausal life. ULs, also called myomas or fibroids, cause a substantial health burden through symptoms such as excessive uterine bleeding, abdominal pain and infertility. These tumors are the most common cause of hysterectomy. Considering the impact that ULs have to women’s health, they are severely understudied. Our breakthrough work has shed important new light on the biology and genesis of ULs. In this ERC proposal we hypothesize that ULs can emerge through several distinct mechanisms and anticipate that each mechanism contributes to somewhat different tumor biology, clinicopathological features, and response to treatment. Also, we hypothesize that predisposing genetic variants may confer susceptibility to a particular UL subclass. To test these hypotheses, we shall create multiple layers of high-throughput data on clinicopathologically characterized ULs, including copy number variation, whole genome sequence, gene expression, and methylome profiles. Integration of these data should establish the existence and key characteristics of the different UL subclasses. Finally, we shall examine the effect of currently used drugs as well as new lead compounds in response to treatment, stratified per UL subclass. These efforts will 1) provide biological insight into molecular mechanisms driving the UL genesis and lay the scientific basis of their molecular classification, 2) describe the key characteristics of each class, 3) provide key biomarkers and molecular tools for routine diagnosis of UL subclasses, as well as clues to their targeted treatment, and 4) produce tools for detection of hereditary predisposition to ULs. This ERC project will be an important step towards non-invasive management of ULs. Reaching this goal would benefit hundreds of millions of women.
Summary
Every fourth woman suffers from uterine leiomyomas (ULs) – benign tumors of the uterine smooth muscle wall - at some point in premenopausal life. ULs, also called myomas or fibroids, cause a substantial health burden through symptoms such as excessive uterine bleeding, abdominal pain and infertility. These tumors are the most common cause of hysterectomy. Considering the impact that ULs have to women’s health, they are severely understudied. Our breakthrough work has shed important new light on the biology and genesis of ULs. In this ERC proposal we hypothesize that ULs can emerge through several distinct mechanisms and anticipate that each mechanism contributes to somewhat different tumor biology, clinicopathological features, and response to treatment. Also, we hypothesize that predisposing genetic variants may confer susceptibility to a particular UL subclass. To test these hypotheses, we shall create multiple layers of high-throughput data on clinicopathologically characterized ULs, including copy number variation, whole genome sequence, gene expression, and methylome profiles. Integration of these data should establish the existence and key characteristics of the different UL subclasses. Finally, we shall examine the effect of currently used drugs as well as new lead compounds in response to treatment, stratified per UL subclass. These efforts will 1) provide biological insight into molecular mechanisms driving the UL genesis and lay the scientific basis of their molecular classification, 2) describe the key characteristics of each class, 3) provide key biomarkers and molecular tools for routine diagnosis of UL subclasses, as well as clues to their targeted treatment, and 4) produce tools for detection of hereditary predisposition to ULs. This ERC project will be an important step towards non-invasive management of ULs. Reaching this goal would benefit hundreds of millions of women.
Max ERC Funding
2 499 099 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym PeptiCrad
Project Personalized oncolytic vaccines for cancer immunotherapy
Researcher (PI) Vincenzo Cerullo
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Consolidator Grant (CoG), LS7, ERC-2015-CoG
Summary This grant application proposes to develop a novel, customizable and personalized anti-cancer vaccine: peptide-coated conditionally replicating adenovirus (PeptiCrad).
Anti-cancer vaccines represent a promising approach for cancer treatment because they elicit durable and specific immune response that destroys primary tumors and distant metastases. Oncolytic viruses (OVs) are of significant interest because in addition to cytolysis they stimulate anti-tumor immune responses, thereby functioning as anti-tumor vaccines. However, their efficacy among cancer patients has been modest. One reason for this shortcoming is that the immune responses generated by virus infection primarily target the virus rather than the tumor. In addition, tumors differ across patients. Specific and personalized approaches (rather than generic virus infection strategies) are required to optimize therapy. To this end we propose to develop a novel vaccine platform that combines the strengths of OVs with the specificity of vaccines. Our technology is called PeptiCrad. PeptiCrad is a virus “dressed as a tumor”. It directly kills cancer cells (i.e., oncolytic viruses) and expresses immunomodulatory molecules (i.e., cytokines or the immune checkpoint inhibitors anti-CTLA4 or anti-PDL1); most importantly, it diverts immunity toward the tumor (i.e., the capsid becomes covered with MHC-I-restricted tumor-specific peptides).
The method that we have developed to cover the virus with tumor peptides is novel and exceeds current state-of-the-art. Importantly, it is fast and does not require genetic or chemical manipulation of the virus; this feature has a significant impact on the translational capability of the project.
Our preliminary results show great potential but significant questions regarding the development and the personalization of PeptiCrad remain to be studied. In this grant I propose two lines of research, one focused on the development and the other one on the personalization of PeptiCrad.
Summary
This grant application proposes to develop a novel, customizable and personalized anti-cancer vaccine: peptide-coated conditionally replicating adenovirus (PeptiCrad).
Anti-cancer vaccines represent a promising approach for cancer treatment because they elicit durable and specific immune response that destroys primary tumors and distant metastases. Oncolytic viruses (OVs) are of significant interest because in addition to cytolysis they stimulate anti-tumor immune responses, thereby functioning as anti-tumor vaccines. However, their efficacy among cancer patients has been modest. One reason for this shortcoming is that the immune responses generated by virus infection primarily target the virus rather than the tumor. In addition, tumors differ across patients. Specific and personalized approaches (rather than generic virus infection strategies) are required to optimize therapy. To this end we propose to develop a novel vaccine platform that combines the strengths of OVs with the specificity of vaccines. Our technology is called PeptiCrad. PeptiCrad is a virus “dressed as a tumor”. It directly kills cancer cells (i.e., oncolytic viruses) and expresses immunomodulatory molecules (i.e., cytokines or the immune checkpoint inhibitors anti-CTLA4 or anti-PDL1); most importantly, it diverts immunity toward the tumor (i.e., the capsid becomes covered with MHC-I-restricted tumor-specific peptides).
The method that we have developed to cover the virus with tumor peptides is novel and exceeds current state-of-the-art. Importantly, it is fast and does not require genetic or chemical manipulation of the virus; this feature has a significant impact on the translational capability of the project.
Our preliminary results show great potential but significant questions regarding the development and the personalization of PeptiCrad remain to be studied. In this grant I propose two lines of research, one focused on the development and the other one on the personalization of PeptiCrad.
Max ERC Funding
1 975 705 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym SPATIALDYNAMICS
Project Ecological, molecular, and evolutionary spatial dynamics
Researcher (PI) Ilkka Aulis Hanski
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Advanced Grant (AdG), LS8, ERC-2008-AdG
Summary The study of wild populations will benefit of increasing integration of ecological, molecular, genetic, and evolutionary approaches. The Glanville fritillary butterfly has a classic metapopulation in a network of 4,000 habitat patches in the Åland Islands, Finland, within an area of 50 by 70 km, across which population surveys have been conducted since 1993. Taking advantage of the opportunity to sample a few larvae from full-sib groups of gregarious larvae in hundreds of local populations, this project involves large-scale phenotyping and genotyping of individuals across the large metapopulation. The aim is to advance our general understanding of the genetic basis of variation in individual performance and life-time reproductive success (fitness), and the role of ongoing natural selection in population dynamics of species living in fragmented landscapes. For genotyping, we select ~1,000 SNPs from annotated genes in the recently sequenced transcriptome of this species. The same SNPs will be used to construct a pedigree for the entire metapopulation for 4 years. Two broad questions will be addressed: (1) Genetic basis of variation in dispersal, related life-history traits, and life-time reproductive success. This will be studied with association analyses, correlating individual phenotypes and genotypes to identify molecular variation with consequences for individual performance and fitness; and with pedigree analyses of natural populations, relating life-time reproductive success of individual larval groups to their phenotypic and genotypic composition. (2) Spatio-temporal population dynamics, the role of ongoing natural selection and consequences for regional adaptation. The purpose is to investigate the causes and consequences of spatio-temporal variation in population dynamics, including the role of ongoing natural selection. Mathematical modelling will be used to investigate the coupling of ecological and evolutionary dynamics in the spatial context.
Summary
The study of wild populations will benefit of increasing integration of ecological, molecular, genetic, and evolutionary approaches. The Glanville fritillary butterfly has a classic metapopulation in a network of 4,000 habitat patches in the Åland Islands, Finland, within an area of 50 by 70 km, across which population surveys have been conducted since 1993. Taking advantage of the opportunity to sample a few larvae from full-sib groups of gregarious larvae in hundreds of local populations, this project involves large-scale phenotyping and genotyping of individuals across the large metapopulation. The aim is to advance our general understanding of the genetic basis of variation in individual performance and life-time reproductive success (fitness), and the role of ongoing natural selection in population dynamics of species living in fragmented landscapes. For genotyping, we select ~1,000 SNPs from annotated genes in the recently sequenced transcriptome of this species. The same SNPs will be used to construct a pedigree for the entire metapopulation for 4 years. Two broad questions will be addressed: (1) Genetic basis of variation in dispersal, related life-history traits, and life-time reproductive success. This will be studied with association analyses, correlating individual phenotypes and genotypes to identify molecular variation with consequences for individual performance and fitness; and with pedigree analyses of natural populations, relating life-time reproductive success of individual larval groups to their phenotypic and genotypic composition. (2) Spatio-temporal population dynamics, the role of ongoing natural selection and consequences for regional adaptation. The purpose is to investigate the causes and consequences of spatio-temporal variation in population dynamics, including the role of ongoing natural selection. Mathematical modelling will be used to investigate the coupling of ecological and evolutionary dynamics in the spatial context.
Max ERC Funding
2 478 999 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym whyBOTher
Project Why does Clostridium botulinum kill? – In search for botulinum neurotoxin regulators
Researcher (PI) Miia Kristina Lindstrom
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Consolidator Grant (CoG), LS9, ERC-2015-CoG
Summary Bacterial toxins cause devastating diseases in humans and animals, ranging from necrotic enteritis to gas gangrene and tetraplegia. While toxin synthesis probably endows these bacteria with a selective advantage in their natural habitats, toxigenesis is likely to represent a fitness cost. It is thus plausible that mild environments encourage bacteria to give up toxin production, or reduce the number of toxigenic cells in populations. The cellular strategies bacteria use to silence toxin production and to establish stably non-toxigenic subpopulations represent targets for innovative antitoxin and vaccine strategies that can be utilized by the food, feed, medical, and agricultural sectors. I have found the first repressor that blocks the production of the most poisonous substance known to mankind, botulinum neurotoxin (BOT). This toxin, also known as “botox”, kills in nanogram quantities and is produced by the notorious food pathogen, Clostridium botulinum. In whyBOTher, I will extend the knowledge from this single regulator to comprehensive understanding of how C. botulinum cultures coordinate BOT production between single cells and cell subpopulations in response to their physical and social environment, and which genetic and plastic cellular strategies the cells take to attenuate BOT production in short and long term. I will experimentally force evolution of BOT-producing and non-producing cell lines, and explore the genetic, epigenetic, and cellular factors that explain the emergence of the two cell lines. To achieve this goal, I will extend the research on C. botulinum biology in two dimensions: from population level to fluorescent single-cell biology, and from genomic information to functional analysis of regulatory and metabolic networks controlling BOT production. whyBOTher represents an unprecedented research effort into regulation of bacterial toxins, and introduces a shift in paradigm from population-level observations to the life of single bacterial cells.
Summary
Bacterial toxins cause devastating diseases in humans and animals, ranging from necrotic enteritis to gas gangrene and tetraplegia. While toxin synthesis probably endows these bacteria with a selective advantage in their natural habitats, toxigenesis is likely to represent a fitness cost. It is thus plausible that mild environments encourage bacteria to give up toxin production, or reduce the number of toxigenic cells in populations. The cellular strategies bacteria use to silence toxin production and to establish stably non-toxigenic subpopulations represent targets for innovative antitoxin and vaccine strategies that can be utilized by the food, feed, medical, and agricultural sectors. I have found the first repressor that blocks the production of the most poisonous substance known to mankind, botulinum neurotoxin (BOT). This toxin, also known as “botox”, kills in nanogram quantities and is produced by the notorious food pathogen, Clostridium botulinum. In whyBOTher, I will extend the knowledge from this single regulator to comprehensive understanding of how C. botulinum cultures coordinate BOT production between single cells and cell subpopulations in response to their physical and social environment, and which genetic and plastic cellular strategies the cells take to attenuate BOT production in short and long term. I will experimentally force evolution of BOT-producing and non-producing cell lines, and explore the genetic, epigenetic, and cellular factors that explain the emergence of the two cell lines. To achieve this goal, I will extend the research on C. botulinum biology in two dimensions: from population level to fluorescent single-cell biology, and from genomic information to functional analysis of regulatory and metabolic networks controlling BOT production. whyBOTher represents an unprecedented research effort into regulation of bacterial toxins, and introduces a shift in paradigm from population-level observations to the life of single bacterial cells.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
