Projects & Collaborations 29 foundShow per page10 10 20 50 Molecular Mechanisms of Neuronal Synapse Formation Research Project | 1 Project MembersImported from Grants Tool 4698088 Cellular and circuit underpinnings of social and maternal behaviours Research Project | 1 Project MembersNo Description available Development of brain-penetrant MNK inhibitors Research Project | 3 Project MembersMAP-kinase interacting kinases (MNKs) are a novel target for the treatment of autism spectrum disorders. We aim to develop a brain-penetrant, small molecule inhibitor that selectively targets MNKs and alleviates the core symptoms of autism. EMBO Fellowship for Myrto Panopoulou Research Project | 2 Project MembersNo Description available Control of molecular differentiation programs by spontaneous activity in neocortical development Research Project | 1 Project MembersThe formation of sensory cortical circuits in the mammalian brain is largely completed at the onset of sensation, with individual cortical neurons exhibiting specific and selective response properties that undergo only minor refinement thereafter. Before sensation, all sensory systems exhibit spontaneous patterned activity that propagates through ascending sensory pathways to primary cortical areas. The structure and spatio-temporal dynamics of such spontaneous patterned activity are thought to have a major impact on cortical wiring. Simultaneously, with spontaneous activity, transcriptional programs unfold that specify cortical cell types, steer their anatomical projections, and may instruct wiring specificity. Alternative mRNA splicing has emerged as a central post-transcriptional mechanism for expanding the molecular codes for neuronal wiring and synapse specification. Moreover, alterations in alternative splicing programs have been linked to neurodevelopmental disorders, in particular autism. It is unknown how spontaneous activity, transcriptional and - in particular - alternative splicing programs interact to drive neuronal wiring in cortex. In this project, we will use the mouse visual cortex as a model system to address these fundamental questions. In Aim 1, we will use in vivo two-photon calcium imaging of individual neurons to map developmental emergence of spontaneous patterned activity and will correlate spontaneous activity patterns to cell type-specific transcript isoform programs. In Aim 2, we will shift patterns of spontaneous activity in the retina and will develop novel genetic sparse marking approaches to explore the impact of patterned activity on transcript isoform programs and neuronal wiring. In Aim 3, we will uncover mechanisms underlying neuronal activity-dependent alternative splicing regulation by advancing novel genetically targeted in vivo methods for dissecting RNA-protein interactions. Together these experiments will illuminate how spontaneous activity in developing sensory systems instructs alternative splicing programs and will advance our understanding of how developmental processes mediate the acquisition of functional specificity in mature cortical networks. Finally, the results will have a profound impact on the interpretation of alternative splicing and network level defects underlying neurodevelopmental diseases. Selective mRNA Translation Control in Rodent Models Carrying Mutations in Genetic Autism Risk Factors Research Project | 1 Project MembersWith an estimate incidence of 1 in 100 children, autism spectrum disorders represent an enormous burden on the population. These developmental disorders develop in the first years of life and to date no mechanism-based treatments are available to the patients. One of the most fundamental challenges in developing treatments for autism-spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of autism cases. Subsets of risk genes can be grouped into functionally-related pathways, most prominently synaptic proteins, translational regulation, and chromatin modifications. Recent work highlighted an unexpected convergence in pathophysiology between gene products contributing to seemingly distant cellular functions. Thus, findings from model organisms suggest that mutations in autism-associated synaptic components precipitate alterations in translational regulation which resemble dysfunctions emerging from direct genetic alterations in the mRNA translation machinery. Early work conceptualized translational de-regulation as representing "too high" or "too low" levels of translation. However, based on more recent evidence it is now hypothesized that alterations in translation machinery and cell signaling result in a selective translational de-regulation of specific mRNAs which are fundamental drivers of the pathophysiology of the disorders. NCCR Translational Fellowship Research Project | 1 Project MembersAutism Spectrum Disorders (ASD) are neuro-developmental disorders characterized by altered social communication and repetitive behaviors. ASD appear in the first 2 years of life and affect one in 54 children according to estimates from CDC's Autism and Developmental Disabilities Monitoring Network. Autistic patients will often have a normal life span but with significantly higher medical and social support needs throughout their lives. ASD therefore represents a significant social and economic burden on affected individuals and their families. Current pharmacotherapy does not address the core symptoms of the disease. Recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin 1-3 which regulate aspects of social behavior in mammals 4 . However, the vast majority of genetic autism risk factors have no known links to oxytocinergic signaling 5-8 . Studies in rodent models of autism provided evidence that a disruption of translation homeostasis results in impaired plasticity and neurodevelopmental conditions 9-12 . Thus, interventions targeting translational machinery might provide a strategy to treat some forms of autism. In previous studies, we discovered an unexpected convergence of translation homeostasis and oxytocin signaling. We found that pharmacological inhibition of Map Kinase Interacting Kinases (MNKs) restores translational homeostasis, oxytocin receptor responses and social recognition behavior in a rodent model replicating an autism-associated genetic mutation 13 . In the present project, we will seek to extend these findings. We will conduct a comprehensive preclinical evaluation of MNK inhibitors for the treatment of autism. We will examine efficacy in three genetic rodent models of autism and human stem cell-derived neurons in vitro. Specifically, we will focus on a novel, highly specific, brain-penetrant MNK inhibitor (AUM001) which already underwent a phase 1 trial in Healthy Volunteers (ACTRN12620000572965). AUM001 was originally developed for cancer therapy. The goal of this study is to critically evaluate repurposing AUM001 for treatment of autism spectrum disorders and to provide information on suitable biomarkers. Upon successful completion of this project, it should be possible to advance AUM001 to clinical studies in ASD. CANDY - Comorbid Analysis of Neurodevelopmental Disorders and Epilepsy Research Project | 1 Project MembersEarly onset neurodevelopmental disorders (NDDs) are common, frequently co-exist with other disorders, come at very high cost, and significantly reduce lifespan. For example, 10-15% of all people in Europe (i.e. 50 to 75 million individuals) are affected by NDDs such as autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), Intellectual Disability (ID), motor problems and language disorders. Moreover the number of affected individuals will likely increase - given the rising diagnostic rates of ASD and ADHD. The life-time health and economic burden of these NDDs exceeds that of cancer, stroke or dementia (Gustavsson 2011), and is significantly further increased by their frequent overlap in the same individual and lifetime persistence (Thapar 2017, and section 1.3 ). However, research spend on NDDs is less than 1% of that spend on cancer, stroke or dementia. These NDDs are also often associated with non-mental somatic diseases such as epilepsy, allergies, (auto-)immune and gastrointestinal (GI) diseases, motor problems, and visual and auditory handicaps (Muskens 2017, and section 1.3 ). Patients with ASD or ADHD or ID die on average 20 years younger than individuals in the general population, and this is further amplified by somatic multimorbidity, in particular epilepsy (Hirvikoski 2016; Dalsgaard 2015). Currently, there are no effective treatments for core symptoms of ASD and ID. Existing treatments for ADHD are symptomatic and do not affect either the underlying pathophysiology (which is unknown) or improve long-term outcome (Storebø 2015). The solution . There is hope, however. A recent fundamental conceptual shift in thinking about NDDs offers new opportunities. There is compelling evidence that some rare genetic variants (e.g. CNVs) increasing risk for ASD, ADHD, and ID are shared (Gonzalez-Mantilla 2016; Short 2018) and converge on relatively few final common pathways (Kiser 2015). Many of them impact on synaptic plasticity and glutamate and GABA neurotransmission (i.e., excitatory and inhibitory (E/I) balance ) with downstream effects on brain function, cognitive development and risk for somatic multimorbidity, in particular epilepsy. Moreover, outcomes (i.e., symptom profile and severity) are likely moderated by genomic background and environmental factors acting at different time points (critical periods) (Di Filippo 2008). There is in particular emerging evidence that early maternal immune activation is a shared environmental risk factor across NDDs , and that its effect varies as a function of interactions between genetic and other environmental factors, such as nutrition and stress (al Haddad 2019; Knuesel 2014; Careaga 2016). Prenatal dietary and immunologic factors not only impact the fetal brain, but also affect the microbiota. Recent work suggests that the microbiota could be the missing link between environmental "immune" insults in prenatal life and future NDDs (Kelly 2017; Rudzki 2018; Kang 2018). The interaction between host genetics and gut microbiota could clarify why carrying risk-conferring common variants (i.e. from GWAS) only explain a small part of disease phenotypic variance of NDDs. Basically, carrying "good" bacteria may in principle overcome the deleterious effect of (i.e.) specific monoamine, glutamate or GABA signalling pathways. On the other hand, "bad" (i.e. pathogenic) bacteria could, in the same way, exacerbate symptomatology even if a protective genetic profile is present. This complex pattern of interaction affects not only neurotransmission (and its precursors) but also endocrine and neuroinflammatory processes observed in NDDs, as shown by us (Aarts 2017) and others (Strati 2017). Molecular mechanisms of neuronal synapse formation Research Project | 1 Project MembersThe assembly and function of neuronal circuits in the central nervous system requires an array of selective cell-cell interactions and the establishment of unique cell type-specific properties. Cell surface interactions and recognition events direct cell migration, targeted growth, recognition of appropriate target cells, and the differentiation of pre- and postsynaptic structures. The specific synaptic connections, the functional synaptic properties of individual connections, and the intrinsic properties of individual classes of neuronal cells are fundamental to neuronal circuit function and - ultimately - animal behavior. The aim of our studies is to understand the molecular mechanisms underlying synaptic specificity programs in the central nervous system. In particular, we are focusing on how RNA-regulatory mechanisms contribute to the spatio-temporal control of neuronal gene expression to coordinate choice of synaptic partners and acquisition of the appropriate functional properties of individual synapses and specific neuronal populations. AIMS-2-TRIALS Research Project | 1 Project MembersAutism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition affecting over five million people in the European Union. The combination of core symptoms (deficits in social-communication and repetitive and restricted behaviours and interests) and common comorbidities (e.g. epilepsy and depression) significantly reduces the quality of life and life-span of affected individuals. Currently there are no effective drug treatments for the core symptoms. Key factors that have hampered progress include; 1) limited understanding of the underlying pathophysiolog(ies); 2) lack of successful translation from animal models to humans; 3) testing of drugs with specific actions in biologically heterogeneous populations; 4) limited expertise of many European ASD centres in running large-scale clinical trials; and 5) trial designs (e.g. placebo effects). Our vision, therefore, is to apply a precision medicine approach to ASD and improve patient outcomes by tailoring treatments to a patient's biological profile. Our efforts will build on the achievements of 5 other IMI initiatives, 4 Horizon 2020 networks, and 6 SMEs for the first time to; 1) align global resources to validate and qualify stratification biomarkers from infancy to adulthood; 2) develop objective outcome measures that can be used in trials; 3) create a European-wide clinical trials network that reliably carries out studies able to support filings to the EMA/FDA; 4) carry out better targeted clinical trials linked to other international efforts - including quick wins or "fast fails" of ineffective agents; 5) translate molecular mechanisms and drug effects between preclinical models and particular subtypes of ASD. Together we will bring Europe to the forefront of clinical research in ASD. Also we will provide a sustainable legacy that is accessible by others across the world, attracts industry into ASD, and helps transform healthcare. 123 123
Molecular Mechanisms of Neuronal Synapse Formation Research Project | 1 Project MembersImported from Grants Tool 4698088
Cellular and circuit underpinnings of social and maternal behaviours Research Project | 1 Project MembersNo Description available
Development of brain-penetrant MNK inhibitors Research Project | 3 Project MembersMAP-kinase interacting kinases (MNKs) are a novel target for the treatment of autism spectrum disorders. We aim to develop a brain-penetrant, small molecule inhibitor that selectively targets MNKs and alleviates the core symptoms of autism.
Control of molecular differentiation programs by spontaneous activity in neocortical development Research Project | 1 Project MembersThe formation of sensory cortical circuits in the mammalian brain is largely completed at the onset of sensation, with individual cortical neurons exhibiting specific and selective response properties that undergo only minor refinement thereafter. Before sensation, all sensory systems exhibit spontaneous patterned activity that propagates through ascending sensory pathways to primary cortical areas. The structure and spatio-temporal dynamics of such spontaneous patterned activity are thought to have a major impact on cortical wiring. Simultaneously, with spontaneous activity, transcriptional programs unfold that specify cortical cell types, steer their anatomical projections, and may instruct wiring specificity. Alternative mRNA splicing has emerged as a central post-transcriptional mechanism for expanding the molecular codes for neuronal wiring and synapse specification. Moreover, alterations in alternative splicing programs have been linked to neurodevelopmental disorders, in particular autism. It is unknown how spontaneous activity, transcriptional and - in particular - alternative splicing programs interact to drive neuronal wiring in cortex. In this project, we will use the mouse visual cortex as a model system to address these fundamental questions. In Aim 1, we will use in vivo two-photon calcium imaging of individual neurons to map developmental emergence of spontaneous patterned activity and will correlate spontaneous activity patterns to cell type-specific transcript isoform programs. In Aim 2, we will shift patterns of spontaneous activity in the retina and will develop novel genetic sparse marking approaches to explore the impact of patterned activity on transcript isoform programs and neuronal wiring. In Aim 3, we will uncover mechanisms underlying neuronal activity-dependent alternative splicing regulation by advancing novel genetically targeted in vivo methods for dissecting RNA-protein interactions. Together these experiments will illuminate how spontaneous activity in developing sensory systems instructs alternative splicing programs and will advance our understanding of how developmental processes mediate the acquisition of functional specificity in mature cortical networks. Finally, the results will have a profound impact on the interpretation of alternative splicing and network level defects underlying neurodevelopmental diseases.
Selective mRNA Translation Control in Rodent Models Carrying Mutations in Genetic Autism Risk Factors Research Project | 1 Project MembersWith an estimate incidence of 1 in 100 children, autism spectrum disorders represent an enormous burden on the population. These developmental disorders develop in the first years of life and to date no mechanism-based treatments are available to the patients. One of the most fundamental challenges in developing treatments for autism-spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of autism cases. Subsets of risk genes can be grouped into functionally-related pathways, most prominently synaptic proteins, translational regulation, and chromatin modifications. Recent work highlighted an unexpected convergence in pathophysiology between gene products contributing to seemingly distant cellular functions. Thus, findings from model organisms suggest that mutations in autism-associated synaptic components precipitate alterations in translational regulation which resemble dysfunctions emerging from direct genetic alterations in the mRNA translation machinery. Early work conceptualized translational de-regulation as representing "too high" or "too low" levels of translation. However, based on more recent evidence it is now hypothesized that alterations in translation machinery and cell signaling result in a selective translational de-regulation of specific mRNAs which are fundamental drivers of the pathophysiology of the disorders.
NCCR Translational Fellowship Research Project | 1 Project MembersAutism Spectrum Disorders (ASD) are neuro-developmental disorders characterized by altered social communication and repetitive behaviors. ASD appear in the first 2 years of life and affect one in 54 children according to estimates from CDC's Autism and Developmental Disabilities Monitoring Network. Autistic patients will often have a normal life span but with significantly higher medical and social support needs throughout their lives. ASD therefore represents a significant social and economic burden on affected individuals and their families. Current pharmacotherapy does not address the core symptoms of the disease. Recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin 1-3 which regulate aspects of social behavior in mammals 4 . However, the vast majority of genetic autism risk factors have no known links to oxytocinergic signaling 5-8 . Studies in rodent models of autism provided evidence that a disruption of translation homeostasis results in impaired plasticity and neurodevelopmental conditions 9-12 . Thus, interventions targeting translational machinery might provide a strategy to treat some forms of autism. In previous studies, we discovered an unexpected convergence of translation homeostasis and oxytocin signaling. We found that pharmacological inhibition of Map Kinase Interacting Kinases (MNKs) restores translational homeostasis, oxytocin receptor responses and social recognition behavior in a rodent model replicating an autism-associated genetic mutation 13 . In the present project, we will seek to extend these findings. We will conduct a comprehensive preclinical evaluation of MNK inhibitors for the treatment of autism. We will examine efficacy in three genetic rodent models of autism and human stem cell-derived neurons in vitro. Specifically, we will focus on a novel, highly specific, brain-penetrant MNK inhibitor (AUM001) which already underwent a phase 1 trial in Healthy Volunteers (ACTRN12620000572965). AUM001 was originally developed for cancer therapy. The goal of this study is to critically evaluate repurposing AUM001 for treatment of autism spectrum disorders and to provide information on suitable biomarkers. Upon successful completion of this project, it should be possible to advance AUM001 to clinical studies in ASD.
CANDY - Comorbid Analysis of Neurodevelopmental Disorders and Epilepsy Research Project | 1 Project MembersEarly onset neurodevelopmental disorders (NDDs) are common, frequently co-exist with other disorders, come at very high cost, and significantly reduce lifespan. For example, 10-15% of all people in Europe (i.e. 50 to 75 million individuals) are affected by NDDs such as autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), Intellectual Disability (ID), motor problems and language disorders. Moreover the number of affected individuals will likely increase - given the rising diagnostic rates of ASD and ADHD. The life-time health and economic burden of these NDDs exceeds that of cancer, stroke or dementia (Gustavsson 2011), and is significantly further increased by their frequent overlap in the same individual and lifetime persistence (Thapar 2017, and section 1.3 ). However, research spend on NDDs is less than 1% of that spend on cancer, stroke or dementia. These NDDs are also often associated with non-mental somatic diseases such as epilepsy, allergies, (auto-)immune and gastrointestinal (GI) diseases, motor problems, and visual and auditory handicaps (Muskens 2017, and section 1.3 ). Patients with ASD or ADHD or ID die on average 20 years younger than individuals in the general population, and this is further amplified by somatic multimorbidity, in particular epilepsy (Hirvikoski 2016; Dalsgaard 2015). Currently, there are no effective treatments for core symptoms of ASD and ID. Existing treatments for ADHD are symptomatic and do not affect either the underlying pathophysiology (which is unknown) or improve long-term outcome (Storebø 2015). The solution . There is hope, however. A recent fundamental conceptual shift in thinking about NDDs offers new opportunities. There is compelling evidence that some rare genetic variants (e.g. CNVs) increasing risk for ASD, ADHD, and ID are shared (Gonzalez-Mantilla 2016; Short 2018) and converge on relatively few final common pathways (Kiser 2015). Many of them impact on synaptic plasticity and glutamate and GABA neurotransmission (i.e., excitatory and inhibitory (E/I) balance ) with downstream effects on brain function, cognitive development and risk for somatic multimorbidity, in particular epilepsy. Moreover, outcomes (i.e., symptom profile and severity) are likely moderated by genomic background and environmental factors acting at different time points (critical periods) (Di Filippo 2008). There is in particular emerging evidence that early maternal immune activation is a shared environmental risk factor across NDDs , and that its effect varies as a function of interactions between genetic and other environmental factors, such as nutrition and stress (al Haddad 2019; Knuesel 2014; Careaga 2016). Prenatal dietary and immunologic factors not only impact the fetal brain, but also affect the microbiota. Recent work suggests that the microbiota could be the missing link between environmental "immune" insults in prenatal life and future NDDs (Kelly 2017; Rudzki 2018; Kang 2018). The interaction between host genetics and gut microbiota could clarify why carrying risk-conferring common variants (i.e. from GWAS) only explain a small part of disease phenotypic variance of NDDs. Basically, carrying "good" bacteria may in principle overcome the deleterious effect of (i.e.) specific monoamine, glutamate or GABA signalling pathways. On the other hand, "bad" (i.e. pathogenic) bacteria could, in the same way, exacerbate symptomatology even if a protective genetic profile is present. This complex pattern of interaction affects not only neurotransmission (and its precursors) but also endocrine and neuroinflammatory processes observed in NDDs, as shown by us (Aarts 2017) and others (Strati 2017).
Molecular mechanisms of neuronal synapse formation Research Project | 1 Project MembersThe assembly and function of neuronal circuits in the central nervous system requires an array of selective cell-cell interactions and the establishment of unique cell type-specific properties. Cell surface interactions and recognition events direct cell migration, targeted growth, recognition of appropriate target cells, and the differentiation of pre- and postsynaptic structures. The specific synaptic connections, the functional synaptic properties of individual connections, and the intrinsic properties of individual classes of neuronal cells are fundamental to neuronal circuit function and - ultimately - animal behavior. The aim of our studies is to understand the molecular mechanisms underlying synaptic specificity programs in the central nervous system. In particular, we are focusing on how RNA-regulatory mechanisms contribute to the spatio-temporal control of neuronal gene expression to coordinate choice of synaptic partners and acquisition of the appropriate functional properties of individual synapses and specific neuronal populations.
AIMS-2-TRIALS Research Project | 1 Project MembersAutism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition affecting over five million people in the European Union. The combination of core symptoms (deficits in social-communication and repetitive and restricted behaviours and interests) and common comorbidities (e.g. epilepsy and depression) significantly reduces the quality of life and life-span of affected individuals. Currently there are no effective drug treatments for the core symptoms. Key factors that have hampered progress include; 1) limited understanding of the underlying pathophysiolog(ies); 2) lack of successful translation from animal models to humans; 3) testing of drugs with specific actions in biologically heterogeneous populations; 4) limited expertise of many European ASD centres in running large-scale clinical trials; and 5) trial designs (e.g. placebo effects). Our vision, therefore, is to apply a precision medicine approach to ASD and improve patient outcomes by tailoring treatments to a patient's biological profile. Our efforts will build on the achievements of 5 other IMI initiatives, 4 Horizon 2020 networks, and 6 SMEs for the first time to; 1) align global resources to validate and qualify stratification biomarkers from infancy to adulthood; 2) develop objective outcome measures that can be used in trials; 3) create a European-wide clinical trials network that reliably carries out studies able to support filings to the EMA/FDA; 4) carry out better targeted clinical trials linked to other international efforts - including quick wins or "fast fails" of ineffective agents; 5) translate molecular mechanisms and drug effects between preclinical models and particular subtypes of ASD. Together we will bring Europe to the forefront of clinical research in ASD. Also we will provide a sustainable legacy that is accessible by others across the world, attracts industry into ASD, and helps transform healthcare.
