Dr. Joseph L. Alcorn, Assistant Professor

molecular mechanisms involved in the regulation of pulmonary surfactant protein gene expression

Pulmonary surfactant is a lipoprotein complex produced exclusively by type II pneumonocytes of the lung alveolus that acts to reduce surface tension at the air/liquid interface and is involved in host-defense of the lung against environmental insults. Expression of surfactant is developmentally regulated and is enhanced by the presence of hormones, such as glucocorticoids. Prematurely born infants in which of synthesis of surfactant is not initiated or is reduced are prone to develop Respiratory Distress Syndrome (RDS), the leading cause of neonatal morbidity and mortality in developed countries.

Research in my laboratory is focused on the molecular mechanisms involved in regulation of expression of two of the major pulmonary surfactant proteins; surfactant protein A (SP-A), which is important in host-defense, and surfactant protein B (SP-B), which is critical in lung function. Glucocorticoids act to increase the rate of transcription of the human SP-A and SP-B. However, glucocorticoids also act post-transcriptionally to affect SP-A and SP-B levels in human lung. Glucocorticoids decrease the stability of SP-A mRNA and to increase the stability of SP-B mRNA. We have determined that the mRNA sequences important in post-transcriptional regulation of SP-B mRNA resides in the 3'-untranslated region (UTR) while others have shown that the 3-UTR of the SP-A mRNA is also important in post-transcriptional regulation. We have shown that regulation is mediated by specific protein:mRNA interactions, and we wish to localize the specific sequences in the 3'UTR of the mRNAs and identify the proteins which bind to these sequences. We are using a variety of in vitro techniques to identify the proteins and sequences involved in the regulatory mechanisms such scanning mutagenesis, mass spectroscopy, and electrophoretic mobility shift assay. The long-term goal of this research is to define molecular mechanisms whereby glucocorticoids regulate surfactant protein gene expression during fetal lung development. Identification of sequences and proteins involved in regulation of surfactant proteins and characterization of the protein interactions that mediate these effects will help define the complex mechanisms whereby glucocorticoids regulate eukaryotic gene expression.

Other interests in the lab involve the regulation of SP-A protein levels and secretion from alveolar type II cells by environmental pathogens. We have found that SP-A mRNA levels increase in type II cells in response to exposure to respiratory syncitial virus (RSV), but the levels of protein decrease both in vitro and in vivo. In addition, secretion of SP-A is reduced. We are presently attempting to define the mechanisms of this reduction, whether it be on activation of the proteasome pathway, endoplasmic reticulum (ER)-associated protein degradation (ERAD), or an effect on the secretory pathway. Identification of the mechanism(s) involved may aid in the devising treatments for individuals afflicted with infectious agents.

Bruce SR, Atkins CL, Colasurdo GN, Alcorn JL. Respiratory Syncytial Virus (RSV) Infection Alters Surfactant Protein-A (SP-A) Expression in Human Pulmonary Epithelial Cells by Reducing Translation Efficiency. Am J Physiol Lung Cell Mol Physiol. 2009 Jun 12. [Epub ahead of print]

Alcorn JL, Merritt TM, Farach-Carson MC, Wang HH, Hecht JT. Ribozyme-mediated reduction of wild-type and mutant cartilage oligomeric matrix protein (COMP) mRNA and protein. RNA. 15:686-695, 2009.

Huang HW, Bi W, Jenkins GN, Alcorn JL. Glucocorticoid regulation of human pulmonary surfactant protein-B mRNA stability involves the 3'-untranslated region. Am J Respir Cell Mol Biol. 38:473-482, 2008.

Vidaeff AC, Ramin SM, Gilstrap LC 3rd, Bishop KD, Alcorn JL. Impact of progesterone on cytokine-stimulated nuclear factor-kappaB signaling in HeLa cells. J Matern Fetal Neonatal Med. 20:23-28, 2007.

Brunelli L, Cieslik KA, Alcorn JL, Vatta M, Baldini A. Peroxisome proliferator-activated receptor-delta upregulates 14-3-3 epsilon in human endothelial cells via CCAAT/enhancer binding protein-beta. Circ Res. 100:e59-71, 2007.

Merritt TM, Bick R, Poindexter BJ, Alcorn JL, Hecht JT. Unique matrix structure in the rough endoplasmic reticulum cisternae of pseudoachondroplasia chondrocytes. Am J Pathol. 170:293-300, 2007.

Merritt TM, Alcorn JL, Haynes R, Hecht JT. Expression of mutant cartilage oligomeric matrix protein in human chondrocytes induces the pseudoachondroplasia phenotype. J Orthop Res. 24:700-707, 2006.

Alcorn, JL, Stark, JM, Chiappetta, CL, Jenkins, G and Colasurdo, GN. Effects of RSV infection on pulmonary surfactant protein SP-A in cultured human type II cells: contrasting consequences on SP-A mRNA and protein. Am J Physiol Lung Cell Mol Physiol. 289:L1113-1122. 2005.

Phokela SS, Peleg S, Moya FR and Alcorn, JL. Regulation of human pulmonary surfactant protein gene expression by 1alpha,25-dihydroxyvitamin D3. Am J Physiol Lung Cell Mol Physiol. 289:L617-626. 2005

Romero EJ, Moya FR, Tuvim MJ and Alcorn JL. Interaction of an artificial surfactant in human pulmonary epithelial cells. Pediatr Pulmonol. 39:167-177. 2005

Stark JM, Khan AM, Chiappetta CL, Xue H, Alcorn JL, Colasurdo GN. Immune and functional role of nitric oxide in a mouse model of respiratory syncytial virus infection. J Infect Dis. 191:387-395. 2005.

Search PubMed for a complete list of Dr. Alcorn's publications.