Weaver Lab

Pathogenesis of Interstitial Lung Disease

The interstitial lung diseases (ILD) are a heterogeneous group of pathologies that include the lethal fibrotic disease idiopathic pulmonary fibrosis (IPF). IPF is a chronic, progressive fibrotic interstitial pneumonia of unknown cause with a median survival of approximately three years. There is no treatment for IPF and no diagnostic procedure to identify at-risk individuals or predict disease progression in asymptomatic patients; further, none of the current animal models mimics the entire disease. For these reasons, generation of an appropriate mouse model of IPF has been the central focus of our research activity.

Mutations in the SFTPC gene are associated with development of interstitial lung disease (ILD) in both children and adults. The SFTPC gene is expressed exclusively in type II epithelial cells, implicating this cell type in the pathogenesis of ILD. We have generated “knockin” mice that express mutant Sftpc alleles and genocopy human patients with ILD / IPF. These animals are being used to characterize the natural history of the disease, identify biomarkers for diagnosis and prediction of disease progression, and develop new treatment strategies.

Related Publications

2015Show

Whitsett JA, Weaver TE. Alveolar development and disease. Am J Respir Cell Mol Biol. 2015 Jul;53(1):1-7.

Whitsett, JA, Wert SE, and Weaver TE. Diseases of Pulmonary Surfactant Homeostasis . Annu Rev Pathol. 2015;10:371-393.

2014Show

Hahn, D. R., C. L. Na, and T. E. Weaver. Reserve autophagic capacity in alveolar epithelia provides a replicative niche for influenza A virus. Am J Respir Cell Mol Biol. 2014 Sep;51(3):400-12.

Fritz, J. M., M. Dong, K. S. Apsley, E. P. Martin, C. L. Na, S. Sitaraman, and T. E. Weaver. Deficiency of the BiP cochaperone ERdj4 causes constitutive endoplasmic reticulum stress and metabolic defects. Mol Biol Cell. 2014 Feb;25(4):431-40.

Blackwell, T. S., A. M. Tager, Z. Borok, B. B. Moore, D. A. Schwartz, K. J. Anstrom, Z. Bar-Joseph, P. Bitterman, M. R. Blackburn, W. Bradford, K. K. Brown, H. A. Chapman, H. R. Collard, G. P. Cosgrove, R. Deterding, R. Doyle, K. R. Flaherty, C. K. Garcia, J. S. Hagood, C. A. Henke, E. Herzog, C. M. Hogaboam, J. C. Horowitz, T. E. J. King, J. E. Loyd, W. E. Lawson, C. B. Marsh, P. W. Noble, I. Noth, D. Sheppard, J. Olsson, L. A. Ortiz, T. G. O’Riordan, T. D. Oury, G. Raghu, J. Roman, P. J. Sime, T. H. Sisson, D. Tschumperlin, S. M. Violette, T. E. Weaver, R. G. Wells, E. S. White, N. Kaminski, F. J. Martinez, T. A. Wynn, V. J. Thannickal, and J. P. Eu. Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report. Am J Respir Crit Care Med. 2014 Jan 15;189(2):214-22.

Fritz, J. M., and T. E. Weaver. The BiP Cochaperone ERdj4 Is Required for B Cell Development and Function. PLoS One. 2014 Sep 15;9(9):e107473.

2012Show

Stewart, G. A., R. Ridsdale, E. P. Martin, C. L. Na, Y. Xu, K. Mandapaka, and T. E. Weaver. 4-Phenylbutyric acid treatment rescues trafficking and processing of a mutant surfactant protein-C. Am J Respir Cell Mol Biol. 2012 47: 324-331.

Young, L. R., P. M. Gulleman, J. P. Bridges, T. E. Weaver, G. H. Deutsch, T. S. Blackwell, and F. X. McCormack. The alveolar epithelium determines susceptibility to lung fibrosis in hermansky-pudlak syndrome. Am J Respir Crit Care Med. 2012 186: 1014-1024.

2010Show

Whitsett JA, Wert SE, Weaver TE. Alveolar Surfactant Homeostasis and the Pathogenesis of Pulmonary Disease. Annu. Rev. Med. 2010 61:105-119.

Conkright, J. J., K. S. Apsley, E. P. Martin, R. Ridsdale, W. R. Rice, C. L. Na, B. Yang, and T. E. Weaver. Nedd4-2-mediated ubiquitination facilitates processing of surfactant protein-C. Am J Respir Cell Mol Biol. 2010 42: 181-189.

2008Show

Korfei M, Ruppert C, Mahavadi P, Henneke I, Markart P, Koch M, Lang G, Fink L, Bohle RM, Seeger W, Weaver TE, Guenther A. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008 178:838-846.

Dong, M., J. P. Bridges, K. Apsley, Y. Xu, and T. E. Weaver. ERdj4 and ERdj5 Are Required for Endoplasmic Reticulum-associated Protein Degradation of Misfolded Surfactant Protein C. Mol Biol Cell. 2008 19: 2620-2630.

Nerelius, C., E. Martin, S. Peng, M. Gustafsson, K. Nordling, T. Weaver, and J. Johansson. Mutations linked to interstitial lung disease can abrogate anti-amyloid function of prosurfactant protein C. Biochem J. 2008 416: 201-209.

Other Significant PublicationsShow

Johansson, H., K. Nordling, T. E. Weaver, and J. Johansson. The Brichos domain-containing C-terminal part of pro-surfactant protein C binds to an unfolded poly-val transmembrane segment. J Biol Chem. 2006 281: 21032-21039.

Bridges JP, Xu Y, Na CL, Wong HR, Weaver TE. Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C. J. Cell Biol. 2006 172:395-407.

Li, J., W. Hosia, A. Hamvas, J. Thyberg, H. Jornvall, T. E. Weaver, and J. Johansson. The N-terminal Propeptide of Lung Surfactant Protein C is Necessary for Biosynthesis and Prevents Unfolding of a Metastable alpha-Helix. J Mol Biol. 2004 338: 857-862.

Johansson, J., T. E. Weaver, and L. O. Tjernberg. Proteolytic generation and aggregation of peptides from transmembrane regions: lung surfactant protein C and amyloid beta-peptide. Cell Mol Life Sci. 2004 61: 326-335.

Li, J., M. Ikegami, C. L. Na, A. Hamvas, Q. Espinassous, R. Chaby, L. M. Nogee, T. E. Weaver, and J. Johansson. N-terminally extended surfactant protein (SP) C isolated from SP-B-deficient children has reduced surface activity and inhibited lipopolysaccharide binding. Biochemistry. 2004 43: 3891-3898.

Bridges JP, Wert SE, Nogee LM, Weaver TE. Expression of a human surfactant protein C mutation associated with interstitial lung disease disrupts lung development in transgenic mice. J. Biol. Chem. 2003 278:52739-52746.

Conkright JJ, Na CL, Weaver TE. Overexpression of surfactant protein-C mature peptide causes neonatal lethality in transgenic mice. Am J Respir Cell Mol Biol. 2003 26:85-90.

Conkright, J. J., J. P. Bridges, C. L. Na, W. F. Voorhout, B. Trapnell, S. W. Glasser, and T. E. Weaver. Secretion of surfactant protein C, an integral membrane protein,requires the N-terminal propeptide. J Biol Chem. 2001 276: 14658-14664.

Normal versus ILD.

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