# Modulation of ribosome velocity as a means to rescue refractory CF-causing variants

> **NIH NIH K99** · EMORY UNIVERSITY · 2021 · $105,424

## Abstract

PROJECT SUMMARY (ABSTRACT)
Cystic fibrosis (CF) is a lethal autosomal recessive disorder caused by mutation of the CF transmembrane
conductance regulator (CFTR). The majority of CF patients harbor at least one copy of the F508del-CFTR
variant, which results in protein misfolding and severe multi-organ damage. An overarching goal of this proposal
is to identify cellular targets that can ameliorate disease phenotype by correcting basic genetic defects resulting
from F508del and less prevalent variants, such as premature truncation codons (PTCs) unresponsive to current
therapy. It has become increasingly evident that CFTR coding sequence alterations not only disrupt primary
protein structure, but also perturb ribosome dynamics, consequent mRNA utilization, and protein
folding/biogenesis. In previous studies, yeast phenomic analyses led to discovery of ribosomal protein (RP)
modules as effectors of F508del-CFTR trafficking. In this context, we have established that Rpl12 (uL11)
depletion rescues the F508del-CFTR defect by reducing rates of translation initiation and elongation, thereby
allowing the ribosome and/or associated chaperones to promote a functional protein conformation. Findings
outlined in the present K99/R00 demonstrate that Rpl12 suppression also corrects a rare PTC, W1282X-CFTR,
to a degree that may benefit patients in the clinic. Thus, we hypothesize that RP silencing alters translational
velocity and/or ribosome fidelity to partially rescue synthesis and assembly of refractory CFTR variants. We
propose three specific aims: (1) characterize the effect(s) of RP inhibition on mutant CFTR biogenesis, (2)
ascertain the mechanism by which RP silencing alters translational kinetics to rescue refractory CFTR variants,
and (3) determine in vivo relevance of RPL12 disruption in transgenic CF mice. We will utilize multidisciplinary
expertise directed towards cellular biology, biochemistry, molecular genetics, and mammalian physiology to
mechanistically address a fundamental hypothesis regarding new ways the ribosome influences protein folding.
The studies are intended to establish translation control as a novel and critical checkpoint during CFTR
processing, and identify specific RPs in addition to Rpl12 that mediate this pathway. Such results will improve
understanding of cystic fibrosis disease mechanism, establish safety of repressing Rpl12 in animal models, and
provide a basis for testing relevance of the strategy in other inherited human disease states. During the funding
period of this award, Dr. Oliver will receive training in CFTR biochemical techniques, ribosome profiling, RNA-
seq, bioinformatics, murine models of CF, and career/professional development. Mentorship in these areas will
prepare her for the independent (R00) phase of the award. Emory University provides a rich environment for
career advancement and leverages state-of-the-art facilities in a highly collaborative academic research center.
Once Dr. Oliver has successfully c...

## Key facts

- **NIH application ID:** 10136714
- **Project number:** 5K99HL151965-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Kathryn E Oliver
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $105,424
- **Award type:** 5
- **Project period:** 2020-04-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136714

## Citation

> US National Institutes of Health, RePORTER application 10136714, Modulation of ribosome velocity as a means to rescue refractory CF-causing variants (5K99HL151965-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10136714. Licensed CC0.

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