Rescue of impaired blood-brain barrier in tuberous sclerosis complex patient derived neurovascular unit / Jacquelyn A. BROWN in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Rescue of impaired blood-brain barrier in tuberous sclerosis complex patient derived neurovascular unit Type de document : texte imprimé Auteurs : Jacquelyn A. BROWN, Auteur ; Shannon L. FALEY, Auteur ; Monika JUDGE, Auteur ; Patricia WARD, Auteur ; Rebecca A. IHRIE, Auteur ; Robert CARSON, Auteur ; Laura ARMSTRONG, Auteur ; Mustafa SAHIN, Auteur ; John P. WIKSWO, Auteur ; Kevin C. ESS, Auteur ; M. Diana NEELY, Auteur Langues : Anglais (eng) Mots-clés : Tuberous Sclerosis/physiopathology/genetics  Humans  Blood-Brain Barrier/physiopathology  Tuberous Sclerosis Complex 2 Protein/genetics  Induced Pluripotent Stem Cells  Sirolimus/pharmacology  Astrocytes/metabolism  Astrocytes  Bbb  Human stem cells  Microfluidics  Rapamycin  Tissue chips  mTOR  Bridgebio, and Aucta. He has served on Scientific Advisory Boards for Novartis,  Roche, Regenxbio, SpringWorks Therapeutics, Jaguar Therapeutics, and Alkermes. Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a multi-system genetic disease that causes benign tumors in the brain and other vital organs. The most debilitating symptoms result from involvement of the central nervous system and lead to a multitude of severe symptoms including seizures, intellectual disability, autism, and behavioral problems. TSC is caused by heterozygous mutations of either the TSC1 or TSC2 gene and dysregulation of mTOR kinase with its multifaceted downstream signaling alterations is central to disease pathogenesis. Although the neurological sequelae of the disease are well established, little is known about how these mutations might affect cellular components and the function of the blood-brain barrier (BBB). METHODS: We generated TSC disease-specific cell models of the BBB by leveraging human induced pluripotent stem cell and microfluidic cell culture technologies. RESULTS: Using microphysiological systems, we demonstrate that a BBB generated from TSC2 heterozygous mutant cells shows increased permeability. This can be rescued by wild type astrocytes or by treatment with rapamycin, an mTOR kinase inhibitor. CONCLUSION: Our results demonstrate the utility of microphysiological systems to study human neurological disorders and advance our knowledge of cell lineages contributing to TSC pathogenesis and informs future therapeutics. En ligne : https://dx.doi.org/10.1186/s11689-024-09543-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Rescue of impaired blood-brain barrier in tuberous sclerosis complex patient derived neurovascular unit [texte imprimé] / Jacquelyn A. BROWN, Auteur ; Shannon L. FALEY, Auteur ; Monika JUDGE, Auteur ; Patricia WARD, Auteur ; Rebecca A. IHRIE, Auteur ; Robert CARSON, Auteur ; Laura ARMSTRONG, Auteur ; Mustafa SAHIN, Auteur ; John P. WIKSWO, Auteur ; Kevin C. ESS, Auteur ; M. Diana NEELY, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Tuberous Sclerosis/physiopathology/genetics  Humans  Blood-Brain Barrier/physiopathology  Tuberous Sclerosis Complex 2 Protein/genetics  Induced Pluripotent Stem Cells  Sirolimus/pharmacology  Astrocytes/metabolism  Astrocytes  Bbb  Human stem cells  Microfluidics  Rapamycin  Tissue chips  mTOR  Bridgebio, and Aucta. He has served on Scientific Advisory Boards for Novartis,  Roche, Regenxbio, SpringWorks Therapeutics, Jaguar Therapeutics, and Alkermes. Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a multi-system genetic disease that causes benign tumors in the brain and other vital organs. The most debilitating symptoms result from involvement of the central nervous system and lead to a multitude of severe symptoms including seizures, intellectual disability, autism, and behavioral problems. TSC is caused by heterozygous mutations of either the TSC1 or TSC2 gene and dysregulation of mTOR kinase with its multifaceted downstream signaling alterations is central to disease pathogenesis. Although the neurological sequelae of the disease are well established, little is known about how these mutations might affect cellular components and the function of the blood-brain barrier (BBB). METHODS: We generated TSC disease-specific cell models of the BBB by leveraging human induced pluripotent stem cell and microfluidic cell culture technologies. RESULTS: Using microphysiological systems, we demonstrate that a BBB generated from TSC2 heterozygous mutant cells shows increased permeability. This can be rescued by wild type astrocytes or by treatment with rapamycin, an mTOR kinase inhibitor. CONCLUSION: Our results demonstrate the utility of microphysiological systems to study human neurological disorders and advance our knowledge of cell lineages contributing to TSC pathogenesis and informs future therapeutics. En ligne : https://dx.doi.org/10.1186/s11689-024-09543-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Tuberous sclerosis complex: everything old is new again / Kevin C. ESS in Journal of Neurodevelopmental Disorders, 1-2 (June 2009)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 1-2 (June 2009) . - p.141-9 Titre : Tuberous sclerosis complex: everything old is new again Type de document : texte imprimé Auteurs : Kevin C. ESS, Auteur Article en page(s) : p.141-9 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Tuberous Sclerosis Complex (TSC) is a multiorgan genetic disease caused by loss of function of either the TSC1 (encodes hamartin) or TSC2 (encodes tuberin) genes. Patients with TSC have benign tumors (hamartomas) in multiple organs though brain involvement is typically the most disabling aspect of the disease as very high rates of neurodevelopmental disorders are seen. While first described well over 120 years ago, recent advances have transformed TSC into a prototypical disorder that exemplifies the methods and potential of molecular medicine. This review will detail historical aspects of TSC and its strong associations with neurodevelopmental disorders focusing on epilepsy and autism. Finally, promising new approaches for the treatment of epilepsy and autism in patients with TSC as well as those in the general population will be discussed. En ligne : http://dx.doi.org/10.1007/s11689-009-9014-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=341 [article] Tuberous sclerosis complex: everything old is new again [texte imprimé] / Kevin C. ESS, Auteur . - p.141-9. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 1-2 (June 2009) . - p.141-9 Index. décimale : PER Périodiques Résumé : Tuberous Sclerosis Complex (TSC) is a multiorgan genetic disease caused by loss of function of either the TSC1 (encodes hamartin) or TSC2 (encodes tuberin) genes. Patients with TSC have benign tumors (hamartomas) in multiple organs though brain involvement is typically the most disabling aspect of the disease as very high rates of neurodevelopmental disorders are seen. While first described well over 120 years ago, recent advances have transformed TSC into a prototypical disorder that exemplifies the methods and potential of molecular medicine. This review will detail historical aspects of TSC and its strong associations with neurodevelopmental disorders focusing on epilepsy and autism. Finally, promising new approaches for the treatment of epilepsy and autism in patients with TSC as well as those in the general population will be discussed. En ligne : http://dx.doi.org/10.1007/s11689-009-9014-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=341

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