# Non-coding RNA structure change in Chronic Obstructive Pulmonary Disease

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $520,208

## Abstract

SUMMARY
Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality in the developed world. Smoking
is an important risk factor for the disease, but genetics determine outcome and disease severity. A significant
and broad challenge in establishing the causal molecular mechanism from genetic association data is the fact
that a majority of COPD-associated variants map to non-coding regions of the human genome. One of the genes
strongly associated with COPD is SERPINA1, which encodes the a-1 antitrypsin protein. The SERPINA1 gene
is remarkably complex: It has eleven splice variants, all of which change the 5'-untranslated region (5'-UTR)
without altering the sequence of the encoded protein. We found that translation efficiencies of the mRNAs varied
by orders of magnitude due to the strengths of upstream RNA structure and of open reading frames (uORFs).
uORFs are found in roughly 50% of human genes and tend to function to reduce translation of the downstream
gene but, other than this observation, are poorly understood mechanistically. We have developed and
parameterized a structure-based leaky scanning model of translation that considers alternative splicing, uORF
Kozak sequence strength, the RNA structure at the initiation site of uORFs, and the efficiency of translation of
the primary open reading frame. We propose in our first aim to define how RNA structure and alternative splicing
control expression of a-1 antitrypsin and extend this approach to two other COPD-associated genes. In our
second aim we will comprehensively characterize the RNA structural elements in the SERPINA1 mRNA 5'-UTRs
and in two other COPD-related mRNAs that control translation efficiency, without and with uORFs. These
experiments will establish accurate and broadly impactful frameworks to define the RNA structural features that
modulate translation efficiency in 5'-UTRs and will refine ribosomal leaky scanning models to better predict
tissue-specific expression of COPD-associated proteins.

## Key facts

- **NIH application ID:** 10159303
- **Project number:** 5R01HL111527-08
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Alain T Laederach
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $520,208
- **Award type:** 5
- **Project period:** 2012-01-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159303

## Citation

> US National Institutes of Health, RePORTER application 10159303, Non-coding RNA structure change in Chronic Obstructive Pulmonary Disease (5R01HL111527-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10159303. Licensed CC0.

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