# Structural Analysis of SERPINA1 RNA in A1AT Deficiency

> **NIH NIH F30** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $36,335

## Abstract

ABSTRACT
Alpha-1 antitrypsin (A1AT) deficiency is one of the most common monogenic diseases in North America and can
lead to emphysema and severe liver disease. Hundreds of disease-associated mutations are known, resulting
in insufficient levels of A1AT in the lungs and pathological aggregation in the liver. A1AT deficiency results in
excessive lung remodeling due to excess local protease activity, while intracellular aggregation leads to liver
destruction. The gene that encodes A1AT, SERPINA1, expresses a large number of mRNA isoforms, all
generated by alternative splicing in the 5′-untranslated region (5′-UTR). Although all SERPINA1 mRNAs encode
exactly the same protein, expression level of the A1AT protein varies substantially from the overall RNA transcript
level in different human tissues, suggesting there is significant post-transcriptional gene regulation. Prior work
proposes that distinct structures in the 5'-UTRs of SERPINA1 enhance or disrupt ribosomal translation.
However, structural models of these motifs have not been developed based on in-cell analyses and the extent
to which these structures regulate endogenous protein translation is relatively unexplored. Thus, understanding
expression of A1AT represents a unique opportunity to define RNA-mediated regulation of lung disease and, in
the long term, develop new classes of RNA-targeted therapeutics.
Through this training proposal, I propose to identify and characterize higher order RNA structures in the 5'-UTR
of SERPINA1 mRNA at single-nucleotide resolution in cells and across different cell types using modern high-
throughput chemical probing methods. The functional importance of newly discovered RNA regulatory structures
will be examined using a high-throughput structural-mutational screen and follow-up functional analyses. This
research will provide training in cell biology, novel chemical RNA structure probing methods, next-generation
sequencing strategies, and computational tools for bioinformatics analyses. I will also participate in mentored
clinical activities focusing on the care of patients with genetic lung diseases. This project will result in a deep
understanding of the role of 5'-UTR structure on gene expression, on the influence of different cellular
environments on RNA structure-mediated gene expression, and on the interplay of mechanistic studies and
opportunities for long-term clinical intervention. These findings will explore RNA as a drug target and define new
potential targets for the treatment of A1AT deficiency. The proposed multidisciplinary training will integrate my
clinical and research interests and prepare me to become a leading physician-scientist in RNA structural biology.

## Key facts

- **NIH application ID:** 9933819
- **Project number:** 5F30HL146174-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Philip Joseph Grayeski
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $36,335
- **Award type:** 5
- **Project period:** 2019-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933819

## Citation

> US National Institutes of Health, RePORTER application 9933819, Structural Analysis of SERPINA1 RNA in A1AT Deficiency (5F30HL146174-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933819. Licensed CC0.

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