# Discovery of novel mechanisms that impact CFTR translation and contribute to cystic fibrosis pathogenesis

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $579,784

## Abstract

Discovery of novel mechanisms that impact CFTR translation and contribute to cystic fibrosis
pathogenesis
Abstract
This project is intended to advance high throughput yeast phenomics technology and provide new mechanistic
information regarding a model genetic disease, cystic fibrosis (CF). When clinically significant mutations in the
CF transmembrane conductance regulator (CFTR) are engineered in a yeast homolog (YOR1), genome-wide
phenomic analysis using the yeast deletion strain library (YDSL) identifies novel pathways that impact CF
molecular phenotype. New experimental targets for CF therapy also result from studies of this type. Under
Specific Aim 1 of the renewal, we show ways in which genome-wide yeast studies can advance understanding
of CFTR variants including nonsense (Type 1) and severe folding (Type 2) defects for which no “personalized”
modulator treatment currently exists. We also demonstrate phenomics can be applied to elucidate pathways
necessary for pharmacologic rescue. Specific Aim 2 engages leading-edge technology (ribosomal profiling,
deep-sequencing based on modification mapping (Psi-Seq)) to delve deeply into novel (and unexpected)
mediators of CFTR biogenesis based on analysis of mammalian translational efficiency. In particular, we
examine the role of ribosomal “collisions” or “queueing” described by phenomic analysis, and mRNA
pseudouridinylation for effects on CFTR translation and protein synthesis. Specific Aim 3, applies innovative
CF cell models to establish clinical significance of findings from Aims 1 and 2. The proposed studies will test
important hypotheses relevant to CF pathogenesis, provide new knowledge regarding translational velocity and
mRNA utilization during CFTR expression, and show that ribosomal collisions and pseudouridinylation
contribute to cystic fibrosis. Our findings will also help advance new targets for treating refractory forms of CF.
Lessons learned from the studies can be applied to many other inherited and serious human illnesses.

## Key facts

- **NIH application ID:** 10367064
- **Project number:** 2R01HL136414-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** JOHN L HARTMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $579,784
- **Award type:** 2
- **Project period:** 2017-12-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367064

## Citation

> US National Institutes of Health, RePORTER application 10367064, Discovery of novel mechanisms that impact CFTR translation and contribute to cystic fibrosis pathogenesis (2R01HL136414-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10367064. Licensed CC0.

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