Computational analysis of cortical neuronal excitotoxicity in a large animal model of neonatal brain injury / Panagiotis KRATIMENOS in Journal of Neurodevelopmental Disorders, 14 (2022)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 14 (2022) Titre : Computational analysis of cortical neuronal excitotoxicity in a large animal model of neonatal brain injury Type de document : texte imprimé Auteurs : Panagiotis KRATIMENOS, Auteur ; Abhya VIJ, Auteur ; Robinson VIDVA, Auteur ; Ioannis KOUTROULIS, Auteur ; Maria DELIVORIA-PAPADOPOULOS, Auteur ; Vittorio GALLO, Auteur ; Aaron SATHYANESAN, Auteur Langues : Anglais (eng) Mots-clés : Animals  Animals, Newborn  Brain Injuries/metabolism  Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism  Cerebral Cortex/metabolism  Disease Models, Animal  Humans  Neurons/metabolism  Swine  Calcium/calmodulin  Computational modeling  Excitotoxicity  Neonatal brain injury  Nuclear calcium  SimBiology  Src kinase Index. décimale : PER Périodiques Résumé : BACKGROUND: Neonatal hypoxic brain injury is a major cause of intellectual and developmental disability. Hypoxia causes neuronal dysfunction and death in the developing cerebral cortex due to excitotoxic Ca(2+)-influx. In the translational piglet model of hypoxic encephalopathy, we have previously shown that hypoxia overactivates Ca(2+)/Calmodulin (CaM) signaling via Sarcoma (Src) kinase in cortical neurons, resulting in overexpression of proapoptotic genes. However, identifying the exact relationship between alterations in neuronal Ca(2+)-influx, molecular determinants of cell death, and the degree of hypoxia in a dynamic system represents a significant challenge. METHODS: We used experimental and computational methods to identify molecular events critical to the onset of excitotoxicity-induced apoptosis in the cerebral cortex of newborn piglets. We used 2-3-day-old piglets (normoxic [Nx], hypoxic [Hx], and hypoxic + Src-inhibitor-treatment [Hx+PP2] groups) for biochemical analysis of ATP production, Ca(2+)-influx, and Ca(2+)/CaM-dependent protein kinase kinase 2 (CaMKK2) expression. We then used SimBiology to build a computational model of the Ca(2+)/CaM-Src-kinase signaling cascade, simulating Nx, Hx, and Hx+PP2 conditions. To evaluate our model, we used Sobol variance decomposition, multiparametric global sensitivity analysis, and parameter scanning. RESULTS: Our model captures important molecular trends caused by hypoxia in the piglet brain. Incorporating the action of Src kinase inhibitor PP2 further validated our model and enabled predictive analysis of the effect of hypoxia on CaMKK2. We determined the impact of a feedback loop related to Src phosphorylation of NMDA receptors and activation kinetics of CaMKII. We also identified distinct modes of signaling wherein Ca(2+) level alterations following Src kinase inhibition may not be a linear predictor of changes in Bax expression. Importantly, our model indicates that while pharmacological pre-treatment significantly reduces the onset of abnormal Ca(2+)-influx, there exists a window of intervention after hypoxia during which targeted modulation of Src-NMDAR interaction kinetics in combination with PP2 administration can reduce Ca(2+)-influx and Bax expression to similar levels as pre-treatment. CONCLUSIONS: Our model identifies new dynamics of critical components in the Ca(2+)/CaM-Src signaling pathway leading to neuronal injury and provides a feasible framework for drug efficacy studies in translational models of neonatal brain injury for the prevention of intellectual and developmental disabilities. En ligne : https://dx.doi.org/10.1186/s11689-022-09431-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Computational analysis of cortical neuronal excitotoxicity in a large animal model of neonatal brain injury [texte imprimé] / Panagiotis KRATIMENOS, Auteur ; Abhya VIJ, Auteur ; Robinson VIDVA, Auteur ; Ioannis KOUTROULIS, Auteur ; Maria DELIVORIA-PAPADOPOULOS, Auteur ; Vittorio GALLO, Auteur ; Aaron SATHYANESAN, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 14 (2022) Mots-clés : Animals  Animals, Newborn  Brain Injuries/metabolism  Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism  Cerebral Cortex/metabolism  Disease Models, Animal  Humans  Neurons/metabolism  Swine  Calcium/calmodulin  Computational modeling  Excitotoxicity  Neonatal brain injury  Nuclear calcium  SimBiology  Src kinase Index. décimale : PER Périodiques Résumé : BACKGROUND: Neonatal hypoxic brain injury is a major cause of intellectual and developmental disability. Hypoxia causes neuronal dysfunction and death in the developing cerebral cortex due to excitotoxic Ca(2+)-influx. In the translational piglet model of hypoxic encephalopathy, we have previously shown that hypoxia overactivates Ca(2+)/Calmodulin (CaM) signaling via Sarcoma (Src) kinase in cortical neurons, resulting in overexpression of proapoptotic genes. However, identifying the exact relationship between alterations in neuronal Ca(2+)-influx, molecular determinants of cell death, and the degree of hypoxia in a dynamic system represents a significant challenge. METHODS: We used experimental and computational methods to identify molecular events critical to the onset of excitotoxicity-induced apoptosis in the cerebral cortex of newborn piglets. We used 2-3-day-old piglets (normoxic [Nx], hypoxic [Hx], and hypoxic + Src-inhibitor-treatment [Hx+PP2] groups) for biochemical analysis of ATP production, Ca(2+)-influx, and Ca(2+)/CaM-dependent protein kinase kinase 2 (CaMKK2) expression. We then used SimBiology to build a computational model of the Ca(2+)/CaM-Src-kinase signaling cascade, simulating Nx, Hx, and Hx+PP2 conditions. To evaluate our model, we used Sobol variance decomposition, multiparametric global sensitivity analysis, and parameter scanning. RESULTS: Our model captures important molecular trends caused by hypoxia in the piglet brain. Incorporating the action of Src kinase inhibitor PP2 further validated our model and enabled predictive analysis of the effect of hypoxia on CaMKK2. We determined the impact of a feedback loop related to Src phosphorylation of NMDA receptors and activation kinetics of CaMKII. We also identified distinct modes of signaling wherein Ca(2+) level alterations following Src kinase inhibition may not be a linear predictor of changes in Bax expression. Importantly, our model indicates that while pharmacological pre-treatment significantly reduces the onset of abnormal Ca(2+)-influx, there exists a window of intervention after hypoxia during which targeted modulation of Src-NMDAR interaction kinetics in combination with PP2 administration can reduce Ca(2+)-influx and Bax expression to similar levels as pre-treatment. CONCLUSIONS: Our model identifies new dynamics of critical components in the Ca(2+)/CaM-Src signaling pathway leading to neuronal injury and provides a feasible framework for drug efficacy studies in translational models of neonatal brain injury for the prevention of intellectual and developmental disabilities. En ligne : https://dx.doi.org/10.1186/s11689-022-09431-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

Spatiotemporal development of spinal neuronal and glial populations in the Ts65Dn mouse model of Down syndrome / Nadine M. AZIZ in Journal of Neurodevelopmental Disorders, 11-1 (December 2019)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 11-1 (December 2019) . - 35 Titre : Spatiotemporal development of spinal neuronal and glial populations in the Ts65Dn mouse model of Down syndrome Type de document : texte imprimé Auteurs : Nadine M. AZIZ, Auteur ; Jenny A. KLEIN, Auteur ; Morgan R. BRADY, Auteur ; Jose Luis OLMOS-SERRANO, Auteur ; Vittorio GALLO, Auteur ; Tarik F. HAYDAR, Auteur Article en page(s) : 35 Langues : Anglais (eng) Mots-clés : Animals  Disease Models, Animal  Down Syndrome/physiopathology  Female  Gene Expression Regulation, Developmental  Homeobox Protein Nkx-2.2  Homeodomain Proteins  Male  Mice, Transgenic  Neuroglia/physiology  Neurons/physiology  Nuclear Proteins  Spinal Cord/growth & development  Transcription Factors  White Matter/growth & development Index. décimale : PER Périodiques Résumé : BACKGROUND: Down syndrome (DS), caused by the triplication of chromosome 21, results in a constellation of clinical features including changes in intellectual and motor function. Although altered neural development and function have been well described in people with DS, few studies have investigated the etiology underlying the observed motor phenotypes. Here, we examine the development, patterning, and organization of the spinal cord throughout life in the Ts65Dn mouse, a model that recapitulates many of the motor changes observed in people with DS. METHODS: Spinal cords from embryonic to adult animals were processed for gene and protein expression (immunofluorescence) to track the spatiotemporal development of excitatory and inhibitory neurons and oligodendroglia. Postnatal analyses were focused on the lumbar region due to the reflex and gait abnormalities found in Ts65Dn mice and locomotive alterations seen in people with DS. RESULTS: Between embryonic days E10.5 and E14.5, we found a larger motor neuron progenitor domain in Ts65Dn animals containing more OLIG2-expressing progenitor cells. These disturbed progenitors are delayed in motor neuron production but eventually generate a large number of ISL1+ migrating motor neurons. We found that higher numbers of PAX6+ and NKX2.2+ interneurons (INs) are also produced during this time frame. In the adult lumbar spinal cord, we found an increased level of Hb9 and a decreased level of Irx3 gene expression in trisomic animals. This was accompanied by an increase in Calretinin+ INs, but no changes in other neuronal populations. In aged Ts65Dn animals, both Calbindin+ and ChAT+ neurons were decreased compared to euploid controls. Additionally, in the dorsal corticospinal white matter tract, there were significantly fewer CC1+ mature OLs in 30- and 60-day old trisomic animals and this normalized to euploid levels at 10-11 months. In contrast, the mature OL population was increased in the lateral funiculus, an ascending white matter tract carrying sensory information. In 30-day old animals, we also found a decrease in the number of nodes of Ranvier in both tracts. This decrease normalized both in 60-day old and aged animals. CONCLUSIONS: We show marked changes in both spinal white matter and neuronal composition that change regionally over the life span. In the embryonic Ts65Dn spinal cord, we observe alterations in motor neuron production and migration. In the adult spinal cord, we observe changes in oligodendrocyte maturation and motor neuron loss, the latter of which has also been observed in human spinal cord tissue samples. This work uncovers multiple cellular perturbations during Ts65Dn development and aging, many of which may underlie the motor deficits found in DS. En ligne : https://dx.doi.org/10.1186/s11689-019-9294-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] Spatiotemporal development of spinal neuronal and glial populations in the Ts65Dn mouse model of Down syndrome [texte imprimé] / Nadine M. AZIZ, Auteur ; Jenny A. KLEIN, Auteur ; Morgan R. BRADY, Auteur ; Jose Luis OLMOS-SERRANO, Auteur ; Vittorio GALLO, Auteur ; Tarik F. HAYDAR, Auteur . - 35. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 11-1 (December 2019) . - 35 Mots-clés : Animals  Disease Models, Animal  Down Syndrome/physiopathology  Female  Gene Expression Regulation, Developmental  Homeobox Protein Nkx-2.2  Homeodomain Proteins  Male  Mice, Transgenic  Neuroglia/physiology  Neurons/physiology  Nuclear Proteins  Spinal Cord/growth & development  Transcription Factors  White Matter/growth & development Index. décimale : PER Périodiques Résumé : BACKGROUND: Down syndrome (DS), caused by the triplication of chromosome 21, results in a constellation of clinical features including changes in intellectual and motor function. Although altered neural development and function have been well described in people with DS, few studies have investigated the etiology underlying the observed motor phenotypes. Here, we examine the development, patterning, and organization of the spinal cord throughout life in the Ts65Dn mouse, a model that recapitulates many of the motor changes observed in people with DS. METHODS: Spinal cords from embryonic to adult animals were processed for gene and protein expression (immunofluorescence) to track the spatiotemporal development of excitatory and inhibitory neurons and oligodendroglia. Postnatal analyses were focused on the lumbar region due to the reflex and gait abnormalities found in Ts65Dn mice and locomotive alterations seen in people with DS. RESULTS: Between embryonic days E10.5 and E14.5, we found a larger motor neuron progenitor domain in Ts65Dn animals containing more OLIG2-expressing progenitor cells. These disturbed progenitors are delayed in motor neuron production but eventually generate a large number of ISL1+ migrating motor neurons. We found that higher numbers of PAX6+ and NKX2.2+ interneurons (INs) are also produced during this time frame. In the adult lumbar spinal cord, we found an increased level of Hb9 and a decreased level of Irx3 gene expression in trisomic animals. This was accompanied by an increase in Calretinin+ INs, but no changes in other neuronal populations. In aged Ts65Dn animals, both Calbindin+ and ChAT+ neurons were decreased compared to euploid controls. Additionally, in the dorsal corticospinal white matter tract, there were significantly fewer CC1+ mature OLs in 30- and 60-day old trisomic animals and this normalized to euploid levels at 10-11 months. In contrast, the mature OL population was increased in the lateral funiculus, an ascending white matter tract carrying sensory information. In 30-day old animals, we also found a decrease in the number of nodes of Ranvier in both tracts. This decrease normalized both in 60-day old and aged animals. CONCLUSIONS: We show marked changes in both spinal white matter and neuronal composition that change regionally over the life span. In the embryonic Ts65Dn spinal cord, we observe alterations in motor neuron production and migration. In the adult spinal cord, we observe changes in oligodendrocyte maturation and motor neuron loss, the latter of which has also been observed in human spinal cord tissue samples. This work uncovers multiple cellular perturbations during Ts65Dn development and aging, many of which may underlie the motor deficits found in DS. En ligne : https://dx.doi.org/10.1186/s11689-019-9294-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

Validation of a computational phenotype for finding patients eligible for genetic testing for pathogenic PTEN variants across three centers / Cartik KOTHARI in Journal of Neurodevelopmental Disorders, 14 (2022)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 14 (2022) Titre : Validation of a computational phenotype for finding patients eligible for genetic testing for pathogenic PTEN variants across three centers Type de document : texte imprimé Auteurs : Cartik KOTHARI, Auteur ; Siddharth SRIVASTAVA, Auteur ; Youssef KOUSA, Auteur ; Rima IZEM, Auteur ; Marcin GIERDALSKI, Auteur ; Dongkyu KIM, Auteur ; Amy GOOD, Auteur ; Kira A. DIES, Auteur ; Gregory GEISEL, Auteur ; Hiroki MORIZONO, Auteur ; Vittorio GALLO, Auteur ; Scott L. POMEROY, Auteur ; Gwenn A. GARDEN, Auteur ; Lisa GUAY-WOODFORD, Auteur ; Mustafa SAHIN, Auteur ; Paul AVILLACH, Auteur Langues : Anglais (eng) Mots-clés : Electronic Health Records  Genetic Testing  Hamartoma Syndrome, Multiple/diagnosis/genetics/pathology  Humans  PTEN Phosphohydrolase/genetics  Phenotype  Autism  Computational phenotype  Genetic disease  Rare disease  from GLG, Guidepoint (which connected to a client, Fortress Biotech), and  Novartis. 3. YK has no competing interests to declare. 4. RI has no competing  interests to declare. 5. MG has no competing interests to declare. 6. DK has no  competing interests to declare. 7. AG has no competing interests to declare. 8.  KAD has no competing interests to declare. 9. GG has no competing interests to  declare. 10. HM has no competing interests to declare. 11. VG has no competing  interests to declare. 12. SP has no competing interests to declare. 13. GAG has  no competing interests to declare. 14. LGW has no competing interests to declare.  15. MS reports grant support from Novartis, Roche, Biogen, Astellas, Aeovian,  Bridgebio, Aucta, and Quadrant Biosciences. He has served on Scientific Advisory  Boards for PTEN Research, Novartis, Roche, Celgene, Regenxbio, Alkermes, and  Takeda. 16. PA has no competing interests to declare Index. décimale : PER Périodiques Résumé : BACKGROUND: Computational phenotypes are most often combinations of patient billing codes that are highly predictive of disease using electronic health records (EHR). In the case of rare diseases that can only be diagnosed by genetic testing, computational phenotypes identify patient cohorts for genetic testing and possible diagnosis. This article details the validation of a computational phenotype for PTEN hamartoma tumor syndrome (PHTS) against the EHR of patients at three collaborating clinical research centers: Boston Children's Hospital, Children's National Hospital, and the University of Washington. METHODS: A combination of billing codes from the International Classification of Diseases versions 9 and 10 (ICD-9 and ICD-10) for diagnostic criteria postulated by a research team at Cleveland Clinic was used to identify patient cohorts for genetic testing from the clinical data warehouses at the three research centers. Subsequently, the EHR-including billing codes, clinical notes, and genetic reports-of these patients were reviewed by clinical experts to identify patients with PHTS. RESULTS: The PTEN genetic testing yield of the computational phenotype, the number of patients who needed to be genetically tested for incidence of pathogenic PTEN gene variants, ranged from 82 to 94% at the three centers. CONCLUSIONS: Computational phenotypes have the potential to enable the timely and accurate diagnosis of rare genetic diseases such as PHTS by identifying patient cohorts for genetic sequencing and testing. En ligne : https://dx.doi.org/10.1186/s11689-022-09434-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Validation of a computational phenotype for finding patients eligible for genetic testing for pathogenic PTEN variants across three centers [texte imprimé] / Cartik KOTHARI, Auteur ; Siddharth SRIVASTAVA, Auteur ; Youssef KOUSA, Auteur ; Rima IZEM, Auteur ; Marcin GIERDALSKI, Auteur ; Dongkyu KIM, Auteur ; Amy GOOD, Auteur ; Kira A. DIES, Auteur ; Gregory GEISEL, Auteur ; Hiroki MORIZONO, Auteur ; Vittorio GALLO, Auteur ; Scott L. POMEROY, Auteur ; Gwenn A. GARDEN, Auteur ; Lisa GUAY-WOODFORD, Auteur ; Mustafa SAHIN, Auteur ; Paul AVILLACH, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 14 (2022) Mots-clés : Electronic Health Records  Genetic Testing  Hamartoma Syndrome, Multiple/diagnosis/genetics/pathology  Humans  PTEN Phosphohydrolase/genetics  Phenotype  Autism  Computational phenotype  Genetic disease  Rare disease  from GLG, Guidepoint (which connected to a client, Fortress Biotech), and  Novartis. 3. YK has no competing interests to declare. 4. RI has no competing  interests to declare. 5. MG has no competing interests to declare. 6. DK has no  competing interests to declare. 7. AG has no competing interests to declare. 8.  KAD has no competing interests to declare. 9. GG has no competing interests to  declare. 10. HM has no competing interests to declare. 11. VG has no competing  interests to declare. 12. SP has no competing interests to declare. 13. GAG has  no competing interests to declare. 14. LGW has no competing interests to declare.  15. MS reports grant support from Novartis, Roche, Biogen, Astellas, Aeovian,  Bridgebio, Aucta, and Quadrant Biosciences. He has served on Scientific Advisory  Boards for PTEN Research, Novartis, Roche, Celgene, Regenxbio, Alkermes, and  Takeda. 16. PA has no competing interests to declare Index. décimale : PER Périodiques Résumé : BACKGROUND: Computational phenotypes are most often combinations of patient billing codes that are highly predictive of disease using electronic health records (EHR). In the case of rare diseases that can only be diagnosed by genetic testing, computational phenotypes identify patient cohorts for genetic testing and possible diagnosis. This article details the validation of a computational phenotype for PTEN hamartoma tumor syndrome (PHTS) against the EHR of patients at three collaborating clinical research centers: Boston Children's Hospital, Children's National Hospital, and the University of Washington. METHODS: A combination of billing codes from the International Classification of Diseases versions 9 and 10 (ICD-9 and ICD-10) for diagnostic criteria postulated by a research team at Cleveland Clinic was used to identify patient cohorts for genetic testing from the clinical data warehouses at the three research centers. Subsequently, the EHR-including billing codes, clinical notes, and genetic reports-of these patients were reviewed by clinical experts to identify patients with PHTS. RESULTS: The PTEN genetic testing yield of the computational phenotype, the number of patients who needed to be genetically tested for incidence of pathogenic PTEN gene variants, ranged from 82 to 94% at the three centers. CONCLUSIONS: Computational phenotypes have the potential to enable the timely and accurate diagnosis of rare genetic diseases such as PHTS by identifying patient cohorts for genetic sequencing and testing. En ligne : https://dx.doi.org/10.1186/s11689-022-09434-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

White matter and neurodevelopmental disorders: honoring Jean De Vellis through the work of the NICHD-funded intellectual and developmental disabilities research centers / Heather Cody HAZLETT in Journal of Neurodevelopmental Disorders, 11-1 (December 2019)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 11-1 (December 2019) . - 38 Titre : White matter and neurodevelopmental disorders: honoring Jean De Vellis through the work of the NICHD-funded intellectual and developmental disabilities research centers Type de document : texte imprimé Auteurs : Heather Cody HAZLETT, Auteur ; Vittorio GALLO, Auteur Article en page(s) : 38 Langues : Anglais (eng) Mots-clés : Brain/physiopathology  Humans  Intellectual Disability/complications/physiopathology  National Institute of Child Health and Human Development (U.S.)  Neurodevelopmental Disorders/complications/physiopathology  United States  White Matter/physiopathology Index. décimale : PER Périodiques En ligne : https://dx.doi.org/10.1186/s11689-019-9299-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] White matter and neurodevelopmental disorders: honoring Jean De Vellis through the work of the NICHD-funded intellectual and developmental disabilities research centers [texte imprimé] / Heather Cody HAZLETT, Auteur ; Vittorio GALLO, Auteur . - 38. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 11-1 (December 2019) . - 38 Mots-clés : Brain/physiopathology  Humans  Intellectual Disability/complications/physiopathology  National Institute of Child Health and Human Development (U.S.)  Neurodevelopmental Disorders/complications/physiopathology  United States  White Matter/physiopathology Index. décimale : PER Périodiques En ligne : https://dx.doi.org/10.1186/s11689-019-9299-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

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