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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.
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.
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. epub ahead of print. 2014.
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. 25: 431-440. 2014
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.
189: 214-222. 2014.
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. 47: 324-331. 2012.
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.186: 1014-1024. 2012.
Whitsett JA, Wert SE, Weaver TE. Alveolar Surfactant Homeostasis and the Pathogenesis of Pulmonary Disease. Annu. Rev. Med. 61:105-119. 2010.
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. 42: 181-189. 2010.
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. 178:838-846. 2008.
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. 19: 2620-2630. 2008.
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. 416: 201-209.
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. 281: 21032-21039. 2006.
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. 172:395-407. 2006.
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. 338: 857-862. 2004.
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. 61: 326-335. 2004.
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. 43: 3891-3898. 2004.
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. 278:52739-52746. 2003.
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. 26:85-90. 2002.
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. 276: 14658-14664. 2001.
click to enlarge
Histological sections of normal lung tissue (left panel) and lung tissue from a child with interstitial lung disease (right panel). Note the thickness of the air-blood barrier (tissue between blue arrows).
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