# Understanding tissue selective phenotypes in ribosomopathies with new technologies

> **NIH NIH R21** · STANFORD UNIVERSITY · 2022 · $239,066

## Abstract

In ribosomopathies, perturbed expression of ribosome components leads to tissue-specific phenotypes, such
as limb and craniofacial defects as well as bone marrow failure. What accounts for such tissue-selective
manifestations as a result of mutations in the ribosome, a ubiquitous cellular machine, has remained a
mystery. Our preliminary data strongly support that translational dysfunction may contribute to disease
pathogenesis. In particular, our findings show that translational specificity to gene expression upon RP
haploinsufficiency may arise from an intermediary pathway, the p53-4E-BP1-eIF4E axis, which becomes
activated and links RP haploinsufficiency to selective changes in cap-dependent translation, namely mRNAs
with structured 5’UTRs that require eIF4A helicase activity. This preliminary data strongly supports the
development of technologies that can both examine translational control and protein synthesis within the
hematopoietic compartment that have been previously unattainable to resolve and have limited our
understanding of DBA pathogenesis. Strikingly, while it has been known for over 20 years that RP mutations
lead to bone marrow failure associated with ribosomopathies, there has not been any genome-wide studies to
pinpoint specific translation impairments underlying hematological abnormalities in-vivo. This is at least in part
due to a technical limitation in being able to employ technologies such as ribosome profiling analysis for small
numbers of cells. We propose to close this gap by developing new technologies and state-of-the-art
approaches including low input ribosome profiling, in-vivo 5’UTR RNA structure analysis using a new
technology that we have piloted known as in-cell mutate and map (icM2), and single cell measurements of
protein synthesis. This directly answers to the tool and technology development goals sponsored by this RFA.
In Aim 1, we will utilize a new technology optimized for small cell numbers to characterize the translational
landscape of gene expression for the first time within the hematopoietic compartment of a faithful
ribosomopathy mouse model. This will enable characterization of the global translation landscape of gene
expression underlying hematopoietic dysfunction in vivo in ribosomopathies for the first time. In Aim 2, we will
develop a new technology that we have pioneered known icM2 to address the fundamental question of
whether shared structural features are present in the 5’UTRs of selective mRNAs that account for specificity to
gene expression changes underlying ribosomopathies. This technology has broad reaching implications
because it will allow unprecedented resolution of RNA structures from any cell type. Together, this proposal
will develop state-of-the art technologies, which holds the potential to transform our understanding of an entire
class of human diseases.

## Key facts

- **NIH application ID:** 10506560
- **Project number:** 1R21DK133730-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Maria Barna
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $239,066
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10506560

## Citation

> US National Institutes of Health, RePORTER application 10506560, Understanding tissue selective phenotypes in ribosomopathies with new technologies (1R21DK133730-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10506560. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*