Grants and Contracts Details
Description
UPDATED PROJECT SUMMARY/ABSTRACT
Striated muscle tissue contains the highest mitochondrial content and the largest known proteins,
which present unique challenges to the translational machinery. Muscle tissue specifically expresses
a paralogous ribosomal protein, RLP3L, that is roughly 80% identical to the ubiquitous RPL3, and is
essential to the formation of the large subunit of the ribosome. In muscle, RPL3L substitutes for RPL3
in the ribosome, but how this alters ribosome function remains unknown. Furthermore, these two
paralogs demonstrate an inverse relationship under conditions of muscle adaptation, stress, and
pathology. In dystrophic muscle, RPL3L is lost in favor of RPL3 in the ribosome, but the effects on
muscle functional decline are not understood. Recent evidence suggests that ribosomes can
specialize to selectively translate certain genes into proteins. Additionally, translation control has
emerged as a novel layer of regulation for mitochondrial function, which declines early in the
pathology of muscular dystrophy, prior to an overt phenotype. Taken together, I hypothesize that the
loss of RPL3L in dystrophic muscle impairs ribosome specialization, thus contributing to an imbalance
between mitochondrial and sarcomeric protein synthesis, exacerbating dystrophic disease
progression. Rescue of the muscle specific ribosomal protein in muscular dystrophy will provide the
first evidence for the role of ribosome specialization in muscle functional decline and help guide the
design of new therapeutics. The proposed studies will also, for the first time, investigate the impact of
glucocorticoids (a common therapy for dystrophy) on muscle ribosome specialization and
translational selectivity. Successful completion of the proposed studies will reveal new therapeutic
targets as well as novel mechanisms underlying the pathophysiology of chronic debilitating diseases.
Status | Finished |
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Effective start/end date | 11/1/23 → 10/31/24 |
Funding
- National Institute Arthritis Musculoskeletal & Skin: $336,494.00
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