Identificación de reacciones controladoras en un modelo computacional multi-ómico astrocitario de lipotoxicidad inducida por ácido palmítico
Los astrocitos juegan un papel importante en varios procesos en el cerebro, incluidas condiciones patológicas como las enfermedades neurodegenerativas. Estudios recientes han demostrado que el aumento de ácidos grasos saturados como el ácido palmítico (PA) desencadena vías proinflamatorias en el cer...
- Autores:
-
Angarita Rodríguez, María Andrea
- Tipo de recurso:
- Fecha de publicación:
- 2022
- Institución:
- Universidad Nacional de Colombia
- Repositorio:
- Universidad Nacional de Colombia
- Idioma:
- spa
- OAI Identifier:
- oai:repositorio.unal.edu.co:unal/82354
- Palabra clave:
- 610 - Medicina y salud::616 - Enfermedades
Neuroglia
Células
Cells
Astrocitos
Integración de datos
Ácido palmítico
Modelo computacional
Multi-ómico
Teoría de control
Cavidades farmacológicas
Astrocytes
Data integration
Palmitic acid
Computational model
Multi-omics
Control theory
Drugable cavities
- Rights
- openAccess
- License
- Atribución-NoComercial 4.0 Internacional
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| dc.title.spa.fl_str_mv |
Identificación de reacciones controladoras en un modelo computacional multi-ómico astrocitario de lipotoxicidad inducida por ácido palmítico |
| dc.title.translated.eng.fl_str_mv |
Identification of controlling reactions in a astrocytic multi-omics computational model of palmitic acid-induced lipotoxicity |
| title |
Identificación de reacciones controladoras en un modelo computacional multi-ómico astrocitario de lipotoxicidad inducida por ácido palmítico |
| spellingShingle |
Identificación de reacciones controladoras en un modelo computacional multi-ómico astrocitario de lipotoxicidad inducida por ácido palmítico 610 - Medicina y salud::616 - Enfermedades Neuroglia Células Cells Astrocitos Integración de datos Ácido palmítico Modelo computacional Multi-ómico Teoría de control Cavidades farmacológicas Astrocytes Data integration Palmitic acid Computational model Multi-omics Control theory Drugable cavities |
| title_short |
Identificación de reacciones controladoras en un modelo computacional multi-ómico astrocitario de lipotoxicidad inducida por ácido palmítico |
| title_full |
Identificación de reacciones controladoras en un modelo computacional multi-ómico astrocitario de lipotoxicidad inducida por ácido palmítico |
| title_fullStr |
Identificación de reacciones controladoras en un modelo computacional multi-ómico astrocitario de lipotoxicidad inducida por ácido palmítico |
| title_full_unstemmed |
Identificación de reacciones controladoras en un modelo computacional multi-ómico astrocitario de lipotoxicidad inducida por ácido palmítico |
| title_sort |
Identificación de reacciones controladoras en un modelo computacional multi-ómico astrocitario de lipotoxicidad inducida por ácido palmítico |
| dc.creator.fl_str_mv |
Angarita Rodríguez, María Andrea |
| dc.contributor.advisor.none.fl_str_mv |
Pinzón Velasco, Andres Mauricio |
| dc.contributor.author.none.fl_str_mv |
Angarita Rodríguez, María Andrea |
| dc.contributor.other.none.fl_str_mv |
Janneth González Santos |
| dc.contributor.researchgroup.spa.fl_str_mv |
Grupo de Investigación en Bioinformática y Biología de Sistemas - GIBBS |
| dc.subject.ddc.spa.fl_str_mv |
610 - Medicina y salud::616 - Enfermedades |
| topic |
610 - Medicina y salud::616 - Enfermedades Neuroglia Células Cells Astrocitos Integración de datos Ácido palmítico Modelo computacional Multi-ómico Teoría de control Cavidades farmacológicas Astrocytes Data integration Palmitic acid Computational model Multi-omics Control theory Drugable cavities |
| dc.subject.lemb.spa.fl_str_mv |
Neuroglia Células |
| dc.subject.lemb.eng.fl_str_mv |
Cells |
| dc.subject.proposal.spa.fl_str_mv |
Astrocitos Integración de datos Ácido palmítico Modelo computacional Multi-ómico Teoría de control Cavidades farmacológicas |
| dc.subject.proposal.eng.fl_str_mv |
Astrocytes Data integration Palmitic acid Computational model Multi-omics Control theory Drugable cavities |
| description |
Los astrocitos juegan un papel importante en varios procesos en el cerebro, incluidas condiciones patológicas como las enfermedades neurodegenerativas. Estudios recientes han demostrado que el aumento de ácidos grasos saturados como el ácido palmítico (PA) desencadena vías proinflamatorias en el cerebro. El uso de neuroesteroides sintéticos como la tibolona ha demostrado mecanismos neuroprotectores. Sin embargo, faltan estudios amplios, con un punto de vista sistémico, sobre el papel neurodegenerativo de PA y los mecanismos neuroprotectores de la tibolona. En este estudio, realizamos la integración de datos multiómicos (transcriptoma y proteoma) en un modelo metabólico a escala genómica de astrocitos humanos para estudiar la respuesta astrocitaria durante el tratamiento con palmitato. Evaluamos los flujos metabólicos en tres escenarios (saludable, inflamación inducida por PA y tratamiento con tibolona bajo inflamación por PA). También aplicamos un enfoque de teoría de control para identificar aquellas reacciones que ejercen más control en el sistema astrocítico. Por último, analizamos las cavidades de las enzimas asociadas a estas reacciones para determinar sus potenciales sitios de unión caracterizándolos en función de puntajes de ligandabilidad y capacidad de interacción farmacológica (drogabilidad). Nuestros resultados sugieren que PA genera una modulación del metabolismo central y secundario, mostrando un cambio en el uso de la fuente de energía a través de la inhibición del ciclo del folato, la β-oxidación de ácidos grasos y la regulación positiva de la formación de cuerpos cetónicos. Encontramos 25 interruptores metabólicos bajo regulación celular mediada por PA, 9 de los cuales fueron críticos solo en el escenario inflamatorio pero no en el protector de tibolona. Dentro de estas reacciones, los perfiles de acoplamiento inhibitorio, total y direccional fueron hallazgos clave, que desempeñaron un papel fundamental en la desregulación de las vías metabólicas que pueden aumentar la neurotoxicidad. De los 25 interruptores metabólicos 16 presentaron cavidades potencialmente drogables que, a su vez, contienen el sitio activo de la proteína. En su conjunto, estas 16 enzimas se configuran como potenciales objetivos terapéuticos. Finalmente, el marco general de nuestro enfoque facilitó la comprensión de la regulación metabólica compleja y puede usarse para la exploración in silico de los mecanismos de regulación de las células astrocitarias, y potencialmente de otros tipos celulares, dirigiendo un trabajo experimental futuro más complejo en enfermedades neurodegenerativas. (Texto tomado de la fuente) |
| publishDate |
2022 |
| dc.date.accessioned.none.fl_str_mv |
2022-10-05T23:38:20Z |
| dc.date.available.none.fl_str_mv |
2022-10-05T23:38:20Z |
| dc.date.issued.none.fl_str_mv |
2022-10-04 |
| dc.type.spa.fl_str_mv |
Trabajo de grado - Maestría |
| dc.type.driver.spa.fl_str_mv |
info:eu-repo/semantics/masterThesis |
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info:eu-repo/semantics/acceptedVersion |
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Text |
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http://purl.org/redcol/resource_type/TM |
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acceptedVersion |
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https://repositorio.unal.edu.co/handle/unal/82354 |
| dc.identifier.instname.spa.fl_str_mv |
Universidad Nacional de Colombia |
| dc.identifier.reponame.spa.fl_str_mv |
Repositorio Institucional Universidad Nacional de Colombia |
| dc.identifier.repourl.spa.fl_str_mv |
https://repositorio.unal.edu.co/ |
| url |
https://repositorio.unal.edu.co/handle/unal/82354 https://repositorio.unal.edu.co/ |
| identifier_str_mv |
Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia |
| dc.language.iso.spa.fl_str_mv |
spa |
| language |
spa |
| dc.relation.references.spa.fl_str_mv |
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Atribución-NoComercial 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Pinzón Velasco, Andres Mauricio5470e24dc3b68e2116a743d851a290f7600Angarita Rodríguez, María Andrea10ca9bd4b9b47048e0cec74bac63525cJanneth González SantosGrupo de Investigación en Bioinformática y Biología de Sistemas - GIBBS2022-10-05T23:38:20Z2022-10-05T23:38:20Z2022-10-04https://repositorio.unal.edu.co/handle/unal/82354Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/Los astrocitos juegan un papel importante en varios procesos en el cerebro, incluidas condiciones patológicas como las enfermedades neurodegenerativas. Estudios recientes han demostrado que el aumento de ácidos grasos saturados como el ácido palmítico (PA) desencadena vías proinflamatorias en el cerebro. El uso de neuroesteroides sintéticos como la tibolona ha demostrado mecanismos neuroprotectores. Sin embargo, faltan estudios amplios, con un punto de vista sistémico, sobre el papel neurodegenerativo de PA y los mecanismos neuroprotectores de la tibolona. En este estudio, realizamos la integración de datos multiómicos (transcriptoma y proteoma) en un modelo metabólico a escala genómica de astrocitos humanos para estudiar la respuesta astrocitaria durante el tratamiento con palmitato. Evaluamos los flujos metabólicos en tres escenarios (saludable, inflamación inducida por PA y tratamiento con tibolona bajo inflamación por PA). También aplicamos un enfoque de teoría de control para identificar aquellas reacciones que ejercen más control en el sistema astrocítico. Por último, analizamos las cavidades de las enzimas asociadas a estas reacciones para determinar sus potenciales sitios de unión caracterizándolos en función de puntajes de ligandabilidad y capacidad de interacción farmacológica (drogabilidad). Nuestros resultados sugieren que PA genera una modulación del metabolismo central y secundario, mostrando un cambio en el uso de la fuente de energía a través de la inhibición del ciclo del folato, la β-oxidación de ácidos grasos y la regulación positiva de la formación de cuerpos cetónicos. Encontramos 25 interruptores metabólicos bajo regulación celular mediada por PA, 9 de los cuales fueron críticos solo en el escenario inflamatorio pero no en el protector de tibolona. Dentro de estas reacciones, los perfiles de acoplamiento inhibitorio, total y direccional fueron hallazgos clave, que desempeñaron un papel fundamental en la desregulación de las vías metabólicas que pueden aumentar la neurotoxicidad. De los 25 interruptores metabólicos 16 presentaron cavidades potencialmente drogables que, a su vez, contienen el sitio activo de la proteína. En su conjunto, estas 16 enzimas se configuran como potenciales objetivos terapéuticos. Finalmente, el marco general de nuestro enfoque facilitó la comprensión de la regulación metabólica compleja y puede usarse para la exploración in silico de los mecanismos de regulación de las células astrocitarias, y potencialmente de otros tipos celulares, dirigiendo un trabajo experimental futuro más complejo en enfermedades neurodegenerativas. (Texto tomado de la fuente)Our results suggest that PA generates a modulation of central and secondary metabolism, showing a change in the use of the energy source through the inhibition of the folate cycle, the β-oxidation of fatty acids and the positive regulation of the formation of fatty acids. ketone bodies. We found 25 metabolic switches under PA-mediated cellular regulation, 9 of which were critical only in the inflammatory but not in the protective tibolone scenario. Within these reactions, inhibitory, total, and directional coupling profiles were key findings, playing a critical role in the dysregulation of metabolic pathways that can increase neurotoxicity. Of the 25 metabolic switches, 16 presented potentially drugable cavities that, in turn, contain the active site of the protein. As a whole, these 16 enzymes are configured as potential therapeutic targets. Finally, the general framework of our approach facilitated the understanding of complex metabolic regulation and can be used for in silico exploration of regulatory mechanisms of astrocytic cells, and potentially other cell types, directing future more complex experimental work in diseases. neurodegenerative Our results suggest that PA generates a modulation of central and secondary metabolism, showing a switch in energy source use through inhibition of folate cycle and fatty acid β-oxidation and upregulation of ketone bodies formation. We found 25 metabolic switches under PA-mediated cellular regulation, 9 of which were critical only in the inflammatory but not in the protective tibolone scenario. Within these reactions, inhibitory, total, and directional coupling profiles were key findings, playing a critical role in the dysregulation of metabolic pathways that can increase neurotoxicity. Of the 25 metabolic switches, 16 presented potentially druggable cavities that, in turn, contain the protein's active site. As a whole, these 16 enzymes are configured as potential therapeutic targets. Finally, the general framework of our approach facilitated the understanding of complex metabolic regulation. It can be used for in silico exploration of regulatory mechanisms of astrocytic cells, and potentially other cell types, directing future more complex experimental work in neurodegenerative diseases.La Pontificia Universidad Javeriana- Sede Bogotá y Minciencias - convocatoria 874 de 2020 “Convocatoria para el Fortalecimiento de Proyectos en Ejecución de CTeI en Ciencias de la Salud con Talento Joven e Impacto Regional” - financiaron el proyecto número 9307, dentro del cual se encuentra enmarcado este trabajo.MaestríaMagíster en BioinformáticaBiología de Sistemas96 páginas + anexosapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Ingeniería - Maestría en BioinformáticaDepartamento de Ingeniería de Sistemas e IndustrialFacultad de IngenieríaBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y salud::616 - EnfermedadesNeurogliaCélulasCellsAstrocitosIntegración de datosÁcido palmíticoModelo computacionalMulti-ómicoTeoría de controlCavidades farmacológicasAstrocytesData integrationPalmitic acidComputational modelMulti-omicsControl theoryDrugable cavitiesIdentificación de reacciones controladoras en un modelo computacional multi-ómico astrocitario de lipotoxicidad inducida por ácido palmíticoIdentification of controlling reactions in a astrocytic multi-omics computational model of palmitic acid-induced lipotoxicityTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMÃ, G. 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Scientific Reports, 6(October), 1–10. https://doi.org/10.1038/srep37646Identificación de reacciones controladoras en un modelo computacional multiómico astrocitario de lipotoxicidad inducida por ácido palmíticoMincienciasPontificia Universidad Javeriana- Sede BogotáInvestigadoresLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/82354/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL1075676303.2022.pdf1075676303.2022.pdfTesis de Maestría en Bioinformáticaapplication/pdf3834321https://repositorio.unal.edu.co/bitstream/unal/82354/2/1075676303.2022.pdf9c49711a1e8ac3c097ff9e558582f33bMD52THUMBNAIL1075676303.2022.pdf.jpg1075676303.2022.pdf.jpgGenerated Thumbnailimage/jpeg4620https://repositorio.unal.edu.co/bitstream/unal/82354/3/1075676303.2022.pdf.jpg4459a8f2e4a70577c2a698db2e33eedaMD53unal/82354oai:repositorio.unal.edu.co:unal/823542023-08-09 23:04:30.336Repositorio Institucional Universidad Nacional de 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