Chronic Obstructive Pulmonary Disease (COPD) remains a leading cause of mortality in the U.S. smoking population. Interestingly, only 15% of smokers develop COPD indicating that there is a strong genetic component to the disease. Mutations in specific genes including SERPINA1, which encodes ?- 1-antitrypsin, are associated with increased risk of developing COPD. Genes exist as DNA (deoxy ribonucleic acid), RNA (ribonucleic acid) and proteins. Using novel computational and experimental techniques that predict and validate RNA structure, we have identified a """"""""RiboSNitch"""""""" associated with COPD in the SERPINA1 non-coding region of the mRNA. A RiboSNitch is a structured element in an RNA that adopts an alternative conformation if a specific, disease-associated SNP (Single Nucleotide Polymorphism) is present. We identified mutations associated with COPD in non-coding regions of SERPINA1 that affect the structure of the mRNA untranslated regions (UTRS). Furthermore, these non-coding regions have highly polymorphic splicing patterns, which we have shown affect RNA structure. We propose to further investigate the role of non-coding RNA structure in COPD. Specifically, we will develop highly predictive models of the SERPINA1 mRNA and determine the efects of mutations on structure and function. This will enable us to correlate genotypic information with the structure and function of the regulatory non-coding regions of genes. By determining the functional consequences of RiboSNitch conformational changes on gene regulation in lung and liver cel types (where SERPINA1 is most highly expressed), we will establish the necessary structure/function relationships to obtain a predictive understanding of the role of SERPINA1 mRNA in COPD.

Public Health Relevance

We propose to investigate the role of RNA (Ribonucleic Acid) structural changes in the non-coding regions of Chronic Obstructive Pulmonary Disease (COPD) associated genes. Specifically, we have identified mutations in the untranslated regions (UTRS) of genes that control the elasticity of lung tissue and increase the risk of developing COPD. We will build experimentally validated computational models that will predict the effects of any mutation on these genes and thus improve our ability to determine COPD predisposition based on genetic sequence.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111527-03
Application #
8586556
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Postow, Lisa
Project Start
2012-01-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
3
Fiscal Year
2014
Total Cost
$324,047
Indirect Cost
$99,047
Name
University of North Carolina Chapel Hill
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Woods, Chanin T; Lackey, Lela; Williams, Benfeard et al. (2017) Comparative Visualization of the RNA Suboptimal Conformational Ensemble In Vivo. Biophys J 113:290-301
Gamache, Eric R; Doh, Jung H; Ritz, Justin et al. (2017) Structure-Function Model for Kissing Loop Interactions That Initiate Dimerization of Ty1 RNA. Viruses 9:
Woods, Chanin Tolson; Laederach, Alain (2017) Classification of RNA structure change by 'gazing' at experimental data. Bioinformatics 33:1647-1655
Ball, Christopher B; Solem, Amanda C; Meganck, Rita M et al. (2017) Impact of RNA structure on ZFP36L2 interaction with luteinizing hormone receptor mRNA. RNA 23:1209-1223
Kutchko, Katrina M; Laederach, Alain (2017) Transcending the prediction paradigm: novel applications of SHAPE to RNA function and evolution. Wiley Interdiscip Rev RNA 8:
Corley, Meredith; Solem, Amanda; Phillips, Gabriela et al. (2017) An RNA structure-mediated, posttranscriptional model of human ?-1-antitrypsin expression. Proc Natl Acad Sci U S A 114:E10244-E10253
Schulmeyer, Kayley H; Diaz, Manisha R; Bair, Thomas B et al. (2016) Primary and Secondary Sequence Structure Requirements for Recognition and Discrimination of Target RNAs by Pseudomonas aeruginosa RsmA and RsmF. J Bacteriol 198:2458-69
Corley, Meredith; Solem, Amanda; Qu, Kun et al. (2015) Detecting riboSNitches with RNA folding algorithms: a genome-wide benchmark. Nucleic Acids Res 43:1859-68
Kutchko, Katrina M; Sanders, Wes; Ziehr, Ben et al. (2015) Multiple conformations are a conserved and regulatory feature of the RB1 5' UTR. RNA 21:1274-85
Blanco, Mario R; Martin, Joshua S; Kahlscheuer, Matthew L et al. (2015) Single Molecule Cluster Analysis dissects splicing pathway conformational dynamics. Nat Methods 12:1077-84

Showing the most recent 10 out of 21 publications