Interstitial pulmonary fibrosis (IPF) has numerous etiologies and afflicts millions of individuals worldwide. Yet, there are no effective preventive agents or therapeutic approaches. This situation is due in large part to a lack of understanding of the fundamental molecular mechanisms that mediate the fibrogenic process. In the work proposed here, we have focused on two peptide factors that have been implicated by numerous researchers as central to the development of IPF. These factors are tumor necrosis factor alpha (TNF-a) and transforming growth factor beta one (TGF-B1). Our previous work and preliminary data show that TNF-a up-regulates the expression of TGF-B1 both in vitro and in vivo, but the basic mechanisms through which TNF-a influences TGF-B1 expression remain undefined. TNF-a has been considered by many to be a """"""""master cytokine"""""""" that controls the expression of a number of biologically relevant molecules. In as much as TGF-B1 is considered to be a primary """"""""fibrogenic factor"""""""", we have set forth the central hypothesis that TNF-a induces TGF-B1 production by transcriptional regulation through the MEK/ERK pathway in lung cells: and the pathway of fibrogenesis mediated by TNF-a through TGF-B1 can be interrupted by specific siRNAs that mediate the degradation of transcripts that code for TNF-a, MP-1- a key component of MEK/ERK phosphorylation, and TGF-B1.
Specific Aim 1 will establish MEK/ERK transduction pathways from TNF-a to TGF-B1 and the transcriptional mechanisms of expression.
Aim 2 will focus on other factors that could up-regulate TGF-B1 through this same pathway; and in Aim 3, we will learn if the epithelial and mesenchymal cells in vivo in the lung exhibit the same transduction and transcriptional pathways in health and disease. These studies will provide specific targets for potential therapeutic approaches through the use of small interfering RNAs (siRNA). Thus, in Aim 4, we will show that an siRNA we have designed blocks endogenous TNF-a gene expression. We propose to use this construct as well as an siRNA that degrades MP1 (a key protein in MEK/ERK phosphorylation), and finally an siRNA that will block TGF-B1 expression, and ultimately the development of IPF in our established animal models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES006766-11
Application #
6822801
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Tinkle, Sally S
Project Start
2004-09-01
Project End
2009-07-31
Budget Start
2004-09-01
Budget End
2005-07-31
Support Year
11
Fiscal Year
2004
Total Cost
$282,150
Indirect Cost
Name
Tulane University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Lin, Rui; Degan, Simone; Theriot, Barbara S et al. (2012) Chronic treatment in vivo with ýý-adrenoceptor agonists induces dysfunction of airway ýý(2) -adrenoceptors and exacerbates lung inflammation in mice. Br J Pharmacol 165:2365-77
Miller, Jeffrey D; Lankford, Susan M; Adler, Kenneth B et al. (2010) Mesenchymal stem cells require MARCKS protein for directed chemotaxis in vitro. Am J Respir Cell Mol Biol 43:253-8
Sullivan, Deborah E; Ferris, Marybeth; Nguyen, Hong et al. (2009) TNF-alpha induces TGF-beta(1) expression in lung fibroblasts at the transcriptional level via AP-1 activation. J Cell Mol Med :
Salazar, Keith D; Lankford, Susan M; Brody, Arnold R (2009) Mesenchymal stem cells produce Wnt isoforms and TGF-beta1 that mediate proliferation and procollagen expression by lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 297:L1002-11
Sullivan, Deborah E; Ferris, Marybeth; Pociask, Derek et al. (2008) The latent form of TGFbeta(1) is induced by TNFalpha through an ERK specific pathway and is activated by asbestos-derived reactive oxygen species in vitro and in vivo. J Immunotoxicol 5:145-9
Spees, Jeffrey L; Pociask, Derek A; Sullivan, Deborah E et al. (2007) Engraftment of bone marrow progenitor cells in a rat model of asbestos-induced pulmonary fibrosis. Am J Respir Crit Care Med 176:385-94
Sullivan, Deborah E; Ferris, MaryBeth; Pociask, Derek et al. (2005) Tumor necrosis factor-alpha induces transforming growth factor-beta1 expression in lung fibroblasts through the extracellular signal-regulated kinase pathway. Am J Respir Cell Mol Biol 32:342-9
Li, Jian; Poovey, Halet G; Rodriguez, Juan Felipe et al. (2004) Effect of platelet-derived growth factor on the development and persistence of asbestos-induced fibroproliferative lung disease. J Environ Pathol Toxicol Oncol 23:253-66
Manuel, Raymond C; Hitomi, Kenichi; Arvai, Andrew S et al. (2004) Reaction intermediates in the catalytic mechanism of Escherichia coli MutY DNA glycosylase. J Biol Chem 279:46930-9
Sanchez, Ana M; Minko, Irina G; Kurtz, Andrew J et al. (2003) Comparative evaluation of the bioreactivity and mutagenic spectra of acrolein-derived alpha-HOPdG and gamma-HOPdG regioisomeric deoxyguanosine adducts. Chem Res Toxicol 16:1019-28

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