Centre d'Information et de documentation du CRA Rhône-Alpes
CRA
Informations pratiques
-
Adresse
Centre d'information et de documentation
du CRA Rhône-Alpes
Centre Hospitalier le Vinatier
bât 211
95, Bd Pinel
69678 Bron CedexHoraires
Lundi au Vendredi
9h00-12h00 13h30-16h00Contact
Tél: +33(0)4 37 91 54 65
Mail
Fax: +33(0)4 37 91 54 37
-
Résultat de la recherche
3 recherche sur le mot-clé 'Disease modeling'
Affiner la recherche Générer le flux rss de la recherche
Partager le résultat de cette recherche Faire une suggestion
in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA
Titre : The iPSC Technology to Study Neurodevelopmental Disorders Type de document : Texte imprimé et/ou numérique Auteurs : Alysson Renato MUOTRI, Auteur Année de publication : 2016 Importance : p.295-300 Langues : Anglais (eng) Mots-clés : Autism spectrum disorders Brain Disease modeling Drug screening Human induced pluripotent stem cells Human neurons Index. décimale : SCI-D SCI-D - Neurosciences Résumé : The inaccessibility of live human brain cells for research has blocked progress toward understanding mechanisms underlying neurodevelopmental disorders. A human model, using reprogrammed patient somatic cells offers an attractive alternative because it captures a patient's genome in a pluripotent stage. Despite current pitfalls, the disease-in-a-dish approach allows dynamic analyses of target cells, offering a unique opportunity to dissect cellular and molecular alterations in a controlled environment. Recent publications have highlighted the use of induced pluripotent stem cells (iPSCs) to model autism spectrum disorders (ASDs). Here, I will discuss the advantages of the iPSC technology to complement and advance the research in ASD. Furthermore, I will review the literature on upcoming innovative technology in tissue engineering and examine how that could be combined with current stem cell practices for a better disease modeling tool and future drug screening. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00018-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301 The iPSC Technology to Study Neurodevelopmental Disorders [Texte imprimé et/ou numérique] / Alysson Renato MUOTRI, Auteur . - 2016 . - p.295-300.
in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA
Langues : Anglais (eng)
Mots-clés : Autism spectrum disorders Brain Disease modeling Drug screening Human induced pluripotent stem cells Human neurons Index. décimale : SCI-D SCI-D - Neurosciences Résumé : The inaccessibility of live human brain cells for research has blocked progress toward understanding mechanisms underlying neurodevelopmental disorders. A human model, using reprogrammed patient somatic cells offers an attractive alternative because it captures a patient's genome in a pluripotent stage. Despite current pitfalls, the disease-in-a-dish approach allows dynamic analyses of target cells, offering a unique opportunity to dissect cellular and molecular alterations in a controlled environment. Recent publications have highlighted the use of induced pluripotent stem cells (iPSCs) to model autism spectrum disorders (ASDs). Here, I will discuss the advantages of the iPSC technology to complement and advance the research in ASD. Furthermore, I will review the literature on upcoming innovative technology in tissue engineering and examine how that could be combined with current stem cell practices for a better disease modeling tool and future drug screening. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00018-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301 Exemplaires
Code-barres Cote Support Localisation Section Disponibilité aucun exemplaire TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling / Pauline MARTIN in Molecular Autism, 11 (2020)
[article]
Titre : TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling Type de document : Texte imprimé et/ou numérique Auteurs : Pauline MARTIN, Auteur ; Vilas WAGH, Auteur ; Surya A. REIS, Auteur ; Serkan ERDIN, Auteur ; Roberta L. BEAUCHAMP, Auteur ; Ghalib SHAIKH, Auteur ; Michael E. TALKOWSKI, Auteur ; Elizabeth THIELE, Auteur ; Steven D. SHERIDAN, Auteur ; Stephen J. HAGGARTY, Auteur ; Vijaya RAMESH, Auteur Article en page(s) : 2 p. Langues : Anglais (eng) Mots-clés : CRISPR/Cas9 Disease modeling Early neurodevelopment Induced pluripotent stem cells mek-erk1/2 MNK1/2-eIF4E Neural progenitor cells tsc1 Tuberous sclerosis complex mTORC1 Therapeutics, Psy Therapeutics, and Souvien Therapeutics, none of who were involved in this study. SDS is a scientific advisor for Outermost Therapeutics, Inc., which played no part in the present study. The other authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with frequent occurrence of epilepsy, autism spectrum disorder (ASD), intellectual disability (ID), and tumors in multiple organs. The aberrant activation of mTORC1 in TSC has led to treatment with mTORC1 inhibitor rapamycin as a lifelong therapy for tumors, but TSC-associated neurocognitive manifestations remain unaffected by rapamycin. METHODS: Here, we generated patient-specific, induced pluripotent stem cells (iPSCs) from a TSC patient with a heterozygous, germline, nonsense mutation in exon 15 of TSC1 and established an isogenic set of heterozygous (Het), null and corrected wildtype (Corr-WT) iPSCs using CRISPR/Cas9-mediated gene editing. We differentiated these iPSCs into neural progenitor cells (NPCs) and examined neurodevelopmental phenotypes, signaling and changes in gene expression by RNA-seq. RESULTS: Differentiated NPCs revealed enlarged cell size in TSC1-Het and Null NPCs, consistent with mTORC1 activation. TSC1-Het and Null NPCs also revealed enhanced proliferation and altered neurite outgrowth in a genotype-dependent manner, which was not reversed by rapamycin. Transcriptome analyses of TSC1-NPCs revealed differentially expressed genes that display a genotype-dependent linear response, i.e., genes upregulated/downregulated in Het were further increased/decreased in Null. In particular, genes linked to ASD, epilepsy, and ID were significantly upregulated or downregulated warranting further investigation. In TSC1-Het and Null NPCs, we also observed basal activation of ERK1/2, which was further activated upon rapamycin treatment. Rapamycin also increased MNK1/2-eIF4E signaling in TSC1-deficient NPCs. CONCLUSION: MEK-ERK and MNK-eIF4E pathways regulate protein translation, and our results suggest that aberrant translation distinct in TSC1/2-deficient NPCs could play a role in neurodevelopmental defects. Our data showing upregulation of these signaling pathways by rapamycin support a strategy to combine a MEK or a MNK inhibitor with rapamycin that may be superior for TSC-associated CNS defects. Importantly, our generation of isogenic sets of NPCs from TSC patients provides a valuable platform for translatome and large-scale drug screening studies. Overall, our studies further support the notion that early developmental events such as NPC proliferation and initial process formation, such as neurite number and length that occur prior to neuronal differentiation, represent primary events in neurogenesis critical to disease pathogenesis of neurodevelopmental disorders such as ASD. En ligne : http://dx.doi.org/10.1186/s13229-019-0311-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427
in Molecular Autism > 11 (2020) . - 2 p.[article] TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling [Texte imprimé et/ou numérique] / Pauline MARTIN, Auteur ; Vilas WAGH, Auteur ; Surya A. REIS, Auteur ; Serkan ERDIN, Auteur ; Roberta L. BEAUCHAMP, Auteur ; Ghalib SHAIKH, Auteur ; Michael E. TALKOWSKI, Auteur ; Elizabeth THIELE, Auteur ; Steven D. SHERIDAN, Auteur ; Stephen J. HAGGARTY, Auteur ; Vijaya RAMESH, Auteur . - 2 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 2 p.
Mots-clés : CRISPR/Cas9 Disease modeling Early neurodevelopment Induced pluripotent stem cells mek-erk1/2 MNK1/2-eIF4E Neural progenitor cells tsc1 Tuberous sclerosis complex mTORC1 Therapeutics, Psy Therapeutics, and Souvien Therapeutics, none of who were involved in this study. SDS is a scientific advisor for Outermost Therapeutics, Inc., which played no part in the present study. The other authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with frequent occurrence of epilepsy, autism spectrum disorder (ASD), intellectual disability (ID), and tumors in multiple organs. The aberrant activation of mTORC1 in TSC has led to treatment with mTORC1 inhibitor rapamycin as a lifelong therapy for tumors, but TSC-associated neurocognitive manifestations remain unaffected by rapamycin. METHODS: Here, we generated patient-specific, induced pluripotent stem cells (iPSCs) from a TSC patient with a heterozygous, germline, nonsense mutation in exon 15 of TSC1 and established an isogenic set of heterozygous (Het), null and corrected wildtype (Corr-WT) iPSCs using CRISPR/Cas9-mediated gene editing. We differentiated these iPSCs into neural progenitor cells (NPCs) and examined neurodevelopmental phenotypes, signaling and changes in gene expression by RNA-seq. RESULTS: Differentiated NPCs revealed enlarged cell size in TSC1-Het and Null NPCs, consistent with mTORC1 activation. TSC1-Het and Null NPCs also revealed enhanced proliferation and altered neurite outgrowth in a genotype-dependent manner, which was not reversed by rapamycin. Transcriptome analyses of TSC1-NPCs revealed differentially expressed genes that display a genotype-dependent linear response, i.e., genes upregulated/downregulated in Het were further increased/decreased in Null. In particular, genes linked to ASD, epilepsy, and ID were significantly upregulated or downregulated warranting further investigation. In TSC1-Het and Null NPCs, we also observed basal activation of ERK1/2, which was further activated upon rapamycin treatment. Rapamycin also increased MNK1/2-eIF4E signaling in TSC1-deficient NPCs. CONCLUSION: MEK-ERK and MNK-eIF4E pathways regulate protein translation, and our results suggest that aberrant translation distinct in TSC1/2-deficient NPCs could play a role in neurodevelopmental defects. Our data showing upregulation of these signaling pathways by rapamycin support a strategy to combine a MEK or a MNK inhibitor with rapamycin that may be superior for TSC-associated CNS defects. Importantly, our generation of isogenic sets of NPCs from TSC patients provides a valuable platform for translatome and large-scale drug screening studies. Overall, our studies further support the notion that early developmental events such as NPC proliferation and initial process formation, such as neurite number and length that occur prior to neuronal differentiation, represent primary events in neurogenesis critical to disease pathogenesis of neurodevelopmental disorders such as ASD. En ligne : http://dx.doi.org/10.1186/s13229-019-0311-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 IGF-1 treatment causes unique transcriptional response in neurons from individuals with idiopathic autism / Sara B. LINKER in Molecular Autism, 11 (2020)
[article]
Titre : IGF-1 treatment causes unique transcriptional response in neurons from individuals with idiopathic autism Type de document : Texte imprimé et/ou numérique Auteurs : Sara B. LINKER, Auteur ; Ana P. D. MENDES, Auteur ; Maria C. MARCHETTO, Auteur Article en page(s) : 55 p. Langues : Anglais (eng) Mots-clés : Autism Disease modeling Induced pluripotent stem cells (iPSC) Insulin-like growth factor 1 (IGF-1) Index. décimale : PER Périodiques Résumé : BACKGROUND: Research evidence accumulated in the past years in both rodent and human models for autism spectrum disorders (ASD) have established insulin-like growth factor 1 (IGF-1) as one of the most promising ASD therapeutic interventions to date. ASD is phenotypically and etiologically heterogeneous, making it challenging to uncover the underlying genetic and cellular pathophysiology of the condition; and to efficiently design drugs with widespread clinical benefits. While IGF-1 effects have been comprehensively studied in the literature, how IGF-1 activity may lead to therapeutic recovery in the ASD context is still largely unknown. METHODS: In this study, we used a previously characterized neuronal population derived from induced pluripotent stem cells (iPSC) from neurotypical controls and idiopathic ASD individuals to study the transcriptional signature of acutely and chronically IGF-1-treated cells. RESULTS: We present a comprehensive list of differentially regulated genes and molecular interactions resulting from IGF-1 exposure in developing neurons from controls and ASD individuals. Our results indicate that IGF-1 treatment has a different impact on neurons from ASD patients compared to controls. Response to IGF-1 treatment in neurons derived from ASD patients was heterogeneous and correlated with IGF-1 receptor expression, indicating that IGF-1 response may have responder and non-responder distinctions across cohorts of ASD patients. Our results suggest that caution should be used when predicting the effect of IGF-1 treatment on ASD patients using neurotypical controls. Instead, IGF-1 response should be studied in the context of ASD patients' neural cells. LIMITATIONS: The limitation of our study is that our cohort of eight sporadic ASD individuals is comorbid with macrocephaly in childhood. Future studies will address weather downstream transcriptional response of IGF-1 is comparable in non-macrocephalic ASD cohorts. CONCLUSIONS: The results presented in this study provide an important resource for researchers in the ASD field and underscore the necessity of using ASD patient lines to explore ASD neuronal-specific responses to drugs such as IGF-1. This study further helps to identify candidate pathways and targets for effective clinical intervention and may help to inform clinical trials in the future. En ligne : http://dx.doi.org/10.1186/s13229-020-00359-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427
in Molecular Autism > 11 (2020) . - 55 p.[article] IGF-1 treatment causes unique transcriptional response in neurons from individuals with idiopathic autism [Texte imprimé et/ou numérique] / Sara B. LINKER, Auteur ; Ana P. D. MENDES, Auteur ; Maria C. MARCHETTO, Auteur . - 55 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 55 p.
Mots-clés : Autism Disease modeling Induced pluripotent stem cells (iPSC) Insulin-like growth factor 1 (IGF-1) Index. décimale : PER Périodiques Résumé : BACKGROUND: Research evidence accumulated in the past years in both rodent and human models for autism spectrum disorders (ASD) have established insulin-like growth factor 1 (IGF-1) as one of the most promising ASD therapeutic interventions to date. ASD is phenotypically and etiologically heterogeneous, making it challenging to uncover the underlying genetic and cellular pathophysiology of the condition; and to efficiently design drugs with widespread clinical benefits. While IGF-1 effects have been comprehensively studied in the literature, how IGF-1 activity may lead to therapeutic recovery in the ASD context is still largely unknown. METHODS: In this study, we used a previously characterized neuronal population derived from induced pluripotent stem cells (iPSC) from neurotypical controls and idiopathic ASD individuals to study the transcriptional signature of acutely and chronically IGF-1-treated cells. RESULTS: We present a comprehensive list of differentially regulated genes and molecular interactions resulting from IGF-1 exposure in developing neurons from controls and ASD individuals. Our results indicate that IGF-1 treatment has a different impact on neurons from ASD patients compared to controls. Response to IGF-1 treatment in neurons derived from ASD patients was heterogeneous and correlated with IGF-1 receptor expression, indicating that IGF-1 response may have responder and non-responder distinctions across cohorts of ASD patients. Our results suggest that caution should be used when predicting the effect of IGF-1 treatment on ASD patients using neurotypical controls. Instead, IGF-1 response should be studied in the context of ASD patients' neural cells. LIMITATIONS: The limitation of our study is that our cohort of eight sporadic ASD individuals is comorbid with macrocephaly in childhood. Future studies will address weather downstream transcriptional response of IGF-1 is comparable in non-macrocephalic ASD cohorts. CONCLUSIONS: The results presented in this study provide an important resource for researchers in the ASD field and underscore the necessity of using ASD patient lines to explore ASD neuronal-specific responses to drugs such as IGF-1. This study further helps to identify candidate pathways and targets for effective clinical intervention and may help to inform clinical trials in the future. En ligne : http://dx.doi.org/10.1186/s13229-020-00359-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427