[R01] Deconstructing nuclear speckles contribution to muscle stem cell activation across lifespan
Ente: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Scadenza: 2031-03-31
Importo max: 630.434 EUR
Paese: US
Descrizione
Abstract
Skeletal muscle contains a population of adult stem cells called satellite cells or muscle stem cells (MuSCs)
that are responsible for regeneration after injury. MuSCs utilize gene expression programs to maintain
quiescence and differentiate after injury and a key regulator of gene expression is splicing, which uniquely
changes when transcripts interact with nuclear speckles. Nuclear speckles are membrane-less biomolecular
condensates that phase separate proteins, RNAs and chromatin, but how these organelles regulate molecular
processes in MuSCs remains unknown. Key experiments from our laboratory provide rigorous support for a role
of nuclear speckles and splicing in MuSC function, which were attenuated in old age. The overarching objective
of this program is to establish a systems-based approach to understand how nuclear speckles and alternative
splicing contribute to MuSC programs of activation and regeneration across lifespan. In Aim 1, we will
demonstrate that the loss of a nuclear speckle scaffolding protein, Srrm2, will reduce regenerative potential of
muscle stem cells. In Aim 2, we will establish that increases in oxidative stress from old age attenuate nuclear
speckles and RNA splicing that regulate muscle stem cell activation and repair of muscle injury. In both Aims,
we will use novel transgenic animal models, sophisticated bioinformatics analysis and highly innovative
molecular tools to build a comprehensive and new understanding of nuclear speckles influence on alternative
splicing and stem cell activity. Successful completion of this program will advance our knowledge of fundamental
cell biology for regenerative medicine, and provide a myriad set of insights across molecular, cellular and tissue
scales.
Istituzione: UNIVERSITY OF MICHIGAN AT ANN ARBOR
PI: Carlos A Aguilar
Progetto: 1R01AR087567-01
Settori: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.