Descripción del proyecto
Desvelar los secretos de las características de la interferencia por ARN de los mamíferos
Las infecciones víricas en el genoma suelen producir ARN bicatenario (ARNbc) que puede ser diana de la ribonucleasa III Dicer en la vía de la interferencia por ARN (iARN). Aunque la iARN endógena de los mamíferos está presente, sus características fisiológicas y sus funciones no se conocen del todo. Uno motivos para ello es el procesamiento ineficaz del ARNbc por parte de la Dicer de longitud completa, que contribuye a la latencia de la iARN en mamíferos. Para comprender mejor la función de la iARN en la estirpe germinal y evaluar la actividad antivírica de la iARN para la ganadería intensiva y el tratamiento de personas, el equipo del proyecto D-FENS, financiado por el Consejo Europeo de Investigación, examinará la importancia fisiológica de la parte aminoterminal de Dicer utilizando modelos genéticos animales. El objetivo de esta investigación es descubrir las características específicas de la iARN en cada especie y mejorar nuestra comprensión de sus rasgos comunes y únicos.
Objetivo
Viral infection or retrotransposon expansion in the genome often result in production of double-stranded RNA (dsRNA). dsRNA can be intercepted by RNase III Dicer acting in the RNA interference (RNAi) pathway, an ancient eukaryotic defense mechanism. Notably, endogenous mammalian RNAi appears dormant while its common and unique physiological roles remain poorly understood. A factor underlying mammalian RNAi dormancy is inefficient processing of dsRNA by the full-length Dicer. Yet, a simple truncation of Dicer leads to hyperactive RNAi, which is naturally present in mouse oocytes.
The D-FENS project will use genetic animal models to define common, cell-specific and species-specific roles of mammalian RNAi. D-FENS has three complementary and synergizing objectives:
(1) Explore consequences of hyperactive RNAi in vivo. A mouse expressing a truncated Dicer will reveal at the organismal level any negative effect of hyperactive RNAi, the relationship between RNAi and mammalian immune system, and potential of RNAi to suppress viral infections in mammals.
(2) Define common and species-specific features of RNAi in the oocyte. Functional and bioinformatics analyses in mouse, bovine, and hamster oocytes will define rules and exceptions concerning endogenous RNAi roles, including RNAi contribution to maternal mRNA degradation and co-existence with the miRNA pathway.
(3) Uncover relationship between RNAi and piRNA pathways in suppression of retrotransposons. We hypothesize that hyperactive RNAi in mouse oocytes functionally complements the piRNA pathway, a Dicer-independent pathway suppressing retrotransposons in the germline. Using genetic models, we will explore unique and redundant roles of both pathways in the germline.
D-FENS will uncover physiological significance of the N-terminal part of Dicer, fundamentally improve understanding RNAi function in the germline, and provide a critical in vivo assessment of antiviral activity of RNAi with implications for human therapy.
Ámbito científico
- medical and health sciencesmedical biotechnologygenetic engineering
- medical and health sciencesbasic medicineimmunology
- natural sciencesbiological sciencesgeneticsRNA
- natural sciencesbiological scienceszoologymammalogy
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantivirals
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
142 20 Praha 4
Chequia