Prof. Dr. Peter Scheiffele Department Biozentrum Profiles & Affiliations OverviewResearch Publications Projects & Collaborations Projects & Collaborations OverviewResearch Publications Projects & Collaborations Profiles & Affiliations Projects & Collaborations 33 foundShow per page10 10 20 50 10008188 - Impact of autism spectrum disorder-associated mutations on neuronal mRNA translation Research Project | 1 Project MembersImported from Grants Tool 4721840 Molecular analysis of PBMC and brain samples from TSC patients Research Project | 2 Project MembersImported from Grants Tool 4725241 Transcription Start Site determinants of Neuronal Identity (TSS-NEURO-ID) Research Project | 1 Project MembersImported from Grants Tool 4701871 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. 1234 1...4 OverviewResearch Publications Projects & Collaborations
Projects & Collaborations 33 foundShow per page10 10 20 50 10008188 - Impact of autism spectrum disorder-associated mutations on neuronal mRNA translation Research Project | 1 Project MembersImported from Grants Tool 4721840 Molecular analysis of PBMC and brain samples from TSC patients Research Project | 2 Project MembersImported from Grants Tool 4725241 Transcription Start Site determinants of Neuronal Identity (TSS-NEURO-ID) Research Project | 1 Project MembersImported from Grants Tool 4701871 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. 1234 1...4
10008188 - Impact of autism spectrum disorder-associated mutations on neuronal mRNA translation Research Project | 1 Project MembersImported from Grants Tool 4721840
Molecular analysis of PBMC and brain samples from TSC patients Research Project | 2 Project MembersImported from Grants Tool 4725241
Transcription Start Site determinants of Neuronal Identity (TSS-NEURO-ID) Research Project | 1 Project MembersImported from Grants Tool 4701871
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.
