Cigarette smoking induces oxidative stress and unfolded protein response (UPR), and is the major risk factor for emphysema and COPD (chronic obstructive pulmonary disease) pathophysiology(1-5), although it is not clear why only few smokers develop COPD or why some non-smokers have COPD. We identified that protein levels of AAA (ATPase associated with diverse cellular activities) molecular chaperone and UPR modulator, p97/VCP (Valosin containing protein), are significantly upregulated in COPD peripheral lungs of smokers as compared to non-smokers. We also confirmed that VCP expression correlates with severity of COPD using lung tissues (Lung Tissue Research Consortium, LTRC) from patients with FEV1% predicted of >80 (mild), 50- 80% (moderate) and <50% (severe). In our preliminary experiments, we confirmed that VCP inhibition in HEK293 cells rescues Nrf2 from proteasomal degradation similar to the levels seen with the proteasomal- inhibitor drug, Velcade/PS341. We verified that VCP inhibition not only rescues Nrf2 but also enhances proteasomal activity and antioxidant gene, NQO1 (NAD(P)H quinone oxidoreductase 1) expression. In addition, we and others recently reported that VCP selectively targets the I:B and unfolded proteins over wt- nascent proteins for proteasomal-degradation or aggregation (7-11) and regulates both UPR and proteasomal activities. The goal of this grant is to dissect the mechanisms of VCP-mediated protein processing in COPD and emphysema. The primary hypothesis of this proposal is that VCP regulates UPR, proteasomal activity, and oxidative stress, and is a critical mediator of COPD pathogenesis. A secondary hypothesis is that selective interference of VCP's ERAD function will not only bypass protein-aggregation and uncontrolled UPR but also rescue the other components associated with the pathophysiology of COPD. The overall projected outcome is an identification of a novel therapeutic site that rescues the pathophysiology of COPD and emphysema by modulating UPR, oxidative stress, and chronic inflammatory signaling.
Specific Aim 1 will determine if VCP play a key role in COPD disease pathogenesis. The correlation of VCP expression to proteolytic activities, apoptosis, and oxidative stress and inflammatory markers in control and COPD subjects will help us evaluate if VCP has a critical UPR modifier function in COPD lung disease. We anticipate elucidating the role of VCP in COPD disease pathogenesis.
Specific Aim 2 will evaluate if other components of VCP protein-complex are critical for COPD disease pathogenesis.
We aim to evaluate the physiological role of VCP associated ubiquitin ligases in COPD by correlating there expression and severity of lung disease to proteolytic activities, apoptosis and inflammatory markers (Aim 1). We anticipate identifying the mechanism(s) of VCP and identifying an effective intervention that leads to the normalization of COPD pathophysiology.

Public Health Relevance

The pathogenesis of COPD lung disease remains incompletely understood and current therapies are inadequate. Our preliminary data demonstrate that p97/VCP and proteasomal pathway is critical step in COPD pathogenesis.
We aim to evaluate the regulatory mechanisms of proteasomal pathway in human lungs from COPD subjects. We anticipate improving our understanding of COPD lung disease and contributing to the development of new and better treatments.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Small Research Grants (R03)
Project #
5R03HL096931-02
Application #
7837597
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M1))
Program Officer
Punturieri, Antonello
Project Start
2009-05-11
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
2
Fiscal Year
2010
Total Cost
$82,000
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Bodas, Manish; Min, Taehong; Mazur, Steven et al. (2011) Critical modifier role of membrane-cystic fibrosis transmembrane conductance regulator-dependent ceramide signaling in lung injury and emphysema. J Immunol 186:602-13
Min, Taehong; Bodas, Manish; Mazur, Steven et al. (2011) Critical role of proteostasis-imbalance in pathogenesis of COPD and severe emphysema. J Mol Med (Berl) 89:577-93
Bodas, Manish; Min, Taehong; Vij, Neeraj (2011) Critical role of CFTR-dependent lipid rafts in cigarette smoke-induced lung epithelial injury. Am J Physiol Lung Cell Mol Physiol 300:L811-20
Valle, Christopher W; Min, Taehong; Bodas, Manish et al. (2011) Critical role of VCP/p97 in the pathogenesis and progression of non-small cell lung carcinoma. PLoS One 6:e29073
Vij, Neeraj (2011) Nano-based theranostics for chronic obstructive lung diseases: challenges and therapeutic potential. Expert Opin Drug Deliv 8:1105-9
Kelliher, Clare; Chakravarti, Shukti; Vij, Neeraj et al. (2011) A cellular model for the investigation of Fuchs' endothelial corneal dystrophy. Exp Eye Res 93:880-8
Vij, Neeraj (2011) The case for therapeutic proteostasis modulators. Expert Opin Ther Targets 15:233-6
Belcher, C N; Vij, N (2010) Protein processing and inflammatory signaling in Cystic Fibrosis: challenges and therapeutic strategies. Curr Mol Med 10:82-94
Roy, Indrajit; Vij, Neeraj (2010) Nanodelivery in airway diseases: challenges and therapeutic applications. Nanomedicine 6:237-44
Henderson, Mark J; Vij, Neeraj; Zeitlin, Pamela L (2010) Ubiquitin C-terminal hydrolase-L1 protects cystic fibrosis transmembrane conductance regulator from early stages of proteasomal degradation. J Biol Chem 285:11314-25

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