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- 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.
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.
|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|
|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|
|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|
|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|
|Solem, Amanda C; Halvorsen, Matthew; Ramos, Silvia B V et al. (2015) The potential of the riboSNitch inÂ personalized medicine. Wiley Interdiscip Rev RNA 6:517-32|
|Lackey, Lela; McArthur, Evonne; Laederach, Alain (2015) Increased Transcript Complexity in Genes Associated with Chronic Obstructive Pulmonary Disease. PLoS One 10:e0140885|
|Ramos, Silvia B V; Laederach, Alain (2014) Molecular biology: A second layer of information in RNA. Nature 505:621-2|
|Schlatterer, JÃ¶rg C; Martin, Joshua S; Laederach, Alain et al. (2014) Mapping the kinetic barriers of a Large RNA molecule's folding landscape. PLoS One 9:e85041|
|Rogler, Leslie E; Kosmyna, Brian; Moskowitz, David et al. (2014) Small RNAs derived from lncRNA RNase MRP have gene-silencing activity relevant to human cartilage-hair hypoplasia. Hum Mol Genet 23:368-82|
|Ritz, Justin; Martin, Joshua S; Laederach, Alain (2013) Evolutionary evidence for alternative structure in RNA sequence co-variation. PLoS Comput Biol 9:e1003152|
Showing the most recent 10 out of 14 publications