Identificación de reacciones controladoras en un modelo computacional multi­-ómico astrocitario de lipotoxicidad inducida por ácido palmítico

dc.contributorPinzón Velasco, Andres Mauricio
dc.contributorJanneth González Santos
dc.contributorGrupo de Investigación en Bioinformática y Biología de Sistemas - GIBBS
dc.creatorAngarita Rodríguez, María Andrea
dc.date.accessioned2022-10-05T23:38:20Z
dc.date.accessioned2023-06-06T23:38:01Z
dc.date.available2022-10-05T23:38:20Z
dc.date.available2023-06-06T23:38:01Z
dc.date.created2022-10-05T23:38:20Z
dc.date.issued2022-10-04
dc.identifierhttps://repositorio.unal.edu.co/handle/unal/82354
dc.identifierUniversidad Nacional de Colombia
dc.identifierRepositorio Institucional Universidad Nacional de Colombia
dc.identifierhttps://repositorio.unal.edu.co/
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/6651416
dc.description.abstractLos 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)
dc.description.abstractOur 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.
dc.languagespa
dc.publisherUniversidad Nacional de Colombia
dc.publisherBogotá - Ingeniería - Maestría en Bioinformática
dc.publisherDepartamento de Ingeniería de Sistemas e Industrial
dc.publisherFacultad de Ingeniería
dc.publisherBogotá, Colombia
dc.publisherUniversidad Nacional de Colombia - Sede Bogotá
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dc.rightsAtribución-NoComercial 4.0 Internacional
dc.rightshttp://creativecommons.org/licenses/by-nc/4.0/
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titleIdentificación de reacciones controladoras en un modelo computacional multi­-ómico astrocitario de lipotoxicidad inducida por ácido palmítico
dc.typeTrabajo de grado - Maestría


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