Translational specialization of cellular identity in embryonic development and disease

Descripción del proyecto

Analizar el papel de los factores implicados en la especialización traslacional en las enfermedades cardiacas

Cómo se traduce la información genética en decisiones sobre el destino celular es una cuestión central en la biología del desarrollo. El equipo del proyecto TRANSCEND, financiado por el CEI, investiga cómo las células controlan selectivamente la producción de proteínas en el tiempo y el espacio para impulsar el desarrollo del corazón humano. Centrándose en reguladores especializados de la traslación, en el proyecto se descubrirá cómo estos factores moldean transiciones clave del desarrollo y guían la identidad y función de las células cardiacas. Se combinarán métodos experimentales y computacionales de vanguardia para cartografiar los programas de control traslacional en la salud y la enfermedad y comprobar si pueden aprovecharse para contrarrestar la remodelación cardiaca patológica. Los hallazgos contribuirán al desarrollo de tratamientos innovadores para restaurar la función cardiaca.

Objetivo

A central question in developmental biology is how the genetic information is differentially interpreted to program cell-fate decisions essential for embryogenesis. The success of developmental cell-fate decisions relies on the accurate rewiring of the proteome to support rapid cellular identity changes. Here, we will address the fundamental question: How is the developmental transcriptome differentially translated in time and space to program cell-fate decisions? I hypothesize that the developmental competence for cell-fate decisions is controlled by fate-specific translational specialization factors (TSFs). TSFs program the selective and privileged translation of developmental genes in defined time windows to enable the acquisition of cell fate and maintenance of cellular identity. Notably, in a proof-of-principle study, we discovered that translational specialization in pluripotency poises future lineage choices in humans. The research program TRANSCEND has four work packages: (1) identifying candidate TSFs engineering cardiac fate at critical cell-fate transitions by cell-fate specific, systematic cataloging TSFs on ribosomal complexes; (2) dissecting the molecular and functional role of TSFs in cardiac cell-fate specification by combining targeted CRISPR screens and tethered functional approaches; (3) decoding the mechanisms, modalities, and design principles by which TSFs program cardiac identity by using a holistic approach, including loss-of-function studies in cardiac 2D, organoid, and mouse models along with systems-wide methods such as eCLIP-seq and TCP-seq; and (4) engineering translation specialization modules to ameliorate pathological cardiac hypertrophy using patient-derived in vitro and murine in vivo models. Ultimately, the proposed research program TRANSCEND aims at transforming our current understanding of translational control over cell-fate decisions and opening up innovative avenues for controlled therapeutic restoration of cardiac function.