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Deconstructing in vivo glia-to-neuron conversion

Descripción del proyecto

Mecanismos moleculares y dinámica de la reprogramación de la neuroglia en neuronas «in vivo»

Estudios recientes han demostrado la posibilidad de reprogramar directamente la neuroglia en neuronas «in vivo», lo cual podría permitir en el futuro regenerar las neuronas dañadas por lesiones o enfermedades. Sin embargo, aún no se comprenden del todo los fundamentos moleculares de la conversión de la neuroglia en neuronas. El proyecto Neuro-ReprOmics, financiado por las Acciones Marie Skłodowska-Curie, abordará la cuestión de cómo los factores de reprogramación neurogénica remodelan los programas de expresión génica durante la conversión de neurogliocitos en neuronas inducidas. El estudio empleará combinaciones definidas de factores de reprogramación que permitan la generación de distintos tipos de neuronas, así como el ARN de célula única y ensayos para la secuenciación de la cromatina accesible por la transposasa para elucidar las vías de reprogramación, los mecanismos y los cambios epigenómicos que impulsan el proceso.

Objetivo

Direct lineage reprogramming of cell identity in the nervous system offers the prospect of remodelling diseased brain circuits. Recent years have provided evidence for the possibility of converting brain glia into neurons in vivo. This may eventually allow to regenerate neurons that have degenerated as a consequence of injury or disease. Yet, the process by which glial cells give up their original identity and adopt a neuronal fate remains by large enigmatic. Moreover, the knowledge of molecular underpinnings of glia-to-neuron conversion is lacunary and virtually nothing is known about the process in vivo. The Berninger laboratory has discovered specific cocktails of reprogramming factors that gives rise to induced neurons in the mouse cerebral cortex, with some cells adopting hallmark features of fast-spiking, parvalbumin-expressing interneurons, a neuronal subtype that is highly vulnerable in neuropsychiatric and neurological disorders. The aim of my project addresses the question of how these neurogenic reprogramming factors remodel gene expression programs as glial cells convert into neurons. Thus, I will utilize defined combinations of reprogramming factors leading to the generation the distinct types of neurons to elucidate how and when the reprogramming trajectories diverge. Towards this end, I will establish single cell RNA sequencing as well as scATAC-seq from cells undergoing conversion in vivo to uncover the transcriptomic and epigenomic changes that drive this process. The outcome of this study is twofold, as this will break new ground in our understanding of how transcription factors can overcome existing cell-specific gene expression programs to induce new cellular identities, and at the same time identify new molecular handles for rendering reprogrammed cells more similar to their endogenous counterparts in an attempt to improve the prospects of using this strategy for brain repair.

Coordinador

KING'S COLLEGE LONDON
Aportación neta de la UEn
€ 212 933,76
Dirección
STRAND
WC2R 2LS London
Reino Unido

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Región
London Inner London — West Westminster
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
€ 212 933,76