The long-term goal of this project is to investigate mechanisms of alternative mRNA splicing of human surfactant protein A (SP-A) and potential implications/effects in the pathogenesis of several pulmonary diseases. Alternative mRNA splicing is a major regulatory mechanism that can generate protein diversity and increase proteome complexity. More than 70% of human genes express multiple mRNA variants through alternative splicing. About 20% of the variability from alternative splicing falls within the untranslated regions (5'UTR and 3'UTR) that affects mRNA stability, translation efficiency, and mRNA localization. SP-A, an important innate immune protein, plays a critical role in the innate host defense and the inflammatory regulation of lung, in surfactant-related physiological functions, and in parturition. In humans, there are two functional genes, SP-A1 and SP-A2. Differential expression of SP-A1 and SP-A2 has been observed in fetal and adult lung, and SP-A1 and SP-A2 genetic variants have been associated with pulmonary diseases including respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), and other lung diseases. The 5'UTR of SP-A1 and SP-A2 generates a number of splice variants, and these 5'UTR variants differentially influence translation efficiency and mRNA stability. Moreover, the ratio of SP-A1 to total SP-A content has been shown to vary as a function of age and lung health status. In this proposal, we hypothesize that differences exist between SP-A1 and SP-A2 in 5'UTR cis-acting elements and in trans-acting factors binding these elements. The rationale is based on the observation that: a) the key difference between the most frequently found SP-A1 (A*D') and SP-A2 (A*BD, A*BD') splice variants is the exclusion and inclusion, respectively, of exon B;b) our preliminary findings have shown that SP-A1 cis-acting element #6, i.e. exon splicing enhancer/silencer (ESE/S # 6), plays a role in splicing, and that specific protein(s) may bind to ESE/S #6. To test this hypothesis, we have proposed two specific aims:
Specific Aim #1 : to examine the functional impact of candidate cis-acting ESE/S elements in the SP-A1 and SP-A2 5'UTR splicing.
Specific Aim #2 : to study trans-acting factors involved in the regulation of SP-A 5'UTR splicing, with a focus on binding proteins associated with the SP-A1-specific cis-acting element ESE/S # 6. Upon completion of this R21 project, a novel experimental model system for alternative splicing of human SP-A can be established, and aspects of candidate cis-acting ESE/S elements within each SP-A gene and of trans-acting factors be analyzed and identified. These could provide foundational methodologies and insight for our further studies (R01 application) of the mechanisms involved in the splicing regulation of human SP-A1 and SP-A2, and of better understanding of the pathogenesis of several lung diseases.
This project is to establish a novel high-throughout experimental system for the study of mechanisms of alternative mRNA splicing of human surfactant proteins (SP-A1 and SP-A2). The proposed experiments include examination of the functional impact of candidate cis-acting ESE/S elements and identification of trans-acting factors binding these elements. New methodologies used and knowledge gained will contribute to the growing field of mRNA splicing regulation and to future studies that can help us to better understand the pathogenesis of several lung diseases.
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