Descripción del proyecto
Inestabilidad genómica en células eucariotas: ¿un motor del estado físico?
La leishmania es un parásito protozoario que se transmite a las personas y los animales a través de la picadura de flebótomos infectados, y provoca una serie de enfermedades. A diferencia de la mayoría de las células eucariotas, la leishmania puede aumentar la expresión de genes específicos mediante cambios en la dosis génica a través de la amplificación de cromosomas enteros, regiones cromosómicas o genes individuales. El equipo del proyecto DECOLeishRN, financiado por el Consejo Europeo de Investigación, pretende investigar cómo la leishmania emplea esa inestabilidad del genoma para regular su estado físico. Los investigadores se centrarán en los mecanismos moleculares que pueden filtrar los cambios tóxicos de los beneficiosos en la dosificación de los genes, incluidas las modificaciones del ARN guiadas por ARN no codificantes. Dado que la inestabilidad genómica impulsa el desarrollo del cáncer, los hallazgos del proyecto se extienden más allá de la leishmania.
Objetivo
Darwinian evolution plays a central yet poorly understood role in human disease. Iterations between genetic mutation and environmental selection drive cancer development, microbial infection and therapeutic failure, thus increasing human mortality. The molecular mechanisms that harness the deleterious effects of genome instability to generate beneficial phenotypes in these pathogenic systems are unknown. Here we investigate this important unsolved question in the protozoan parasite Leishmania that causes devastating human infections. In the absence of transcriptional regulation, these early-branching eukaryotes exploit genome instability to regulate expression by gene dosage. Leishmania thus represents an ideal system to investigate how genome instability drives fitness gain in fast evolving, eukaryotic cells, such as observed during cancer development. Synergizing our expertise in genomics, evolution, systems and RNA biology, we have recently made several breakthrough discoveries that link parasite fitness gain to epistatic interactions between co-amplifying genes of small, non-coding RNAs, which program epitranscriptomic and translational regulation. We hypothesize that these genome/RNome interactions generate the phenotypic landscape underlying Leishmania fitness gain. Our proposal investigates this ground-breaking concept through two Specific Aims that (i) combine experimental parasite differentiation and evolution in vitro and in vivo to reveal molecular mechanisms underlying Leishmania predictive adaptation and fitness gain, and (ii) investigate how RNA modification and non-coding RNAs contribute to adaptation by regulating mRNA stability and translational control. Our findings will be highly relevant to other fast growing, eukaryotic systems that rely on genome instability, such as cancer or fungal pathogens.
Ámbito científico
Palabras clave
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-ERC-SYG - HORIZON ERC Synergy GrantsInstitución de acogida
75724 Paris
Francia