The classical renin-angiotensin system (RAS) is an enzymatic cascade producing angiotensin II. This occurs in 2 consecutive steps catalyzed by renin and angiotensin converting enzyme (ACE). The physiologic role of RAS is more complex than simple blood pressure control. It includes a role in tissue injury.
The aim of this grant application is to increase our knowledge about how ACE functions and the roles of its substrates in the control of inflammation and fibrotic diseases. This is important since a disease like pulmonary fibrosis is a serious medical problem affecting more than 200,000 patients and is responsible for over 40,000 deaths annually according to the NHLBI. Presently, there are few treatments available to prevent or reverse the progression of fibrosis. One clinically correlated and well accepted model of lung fibrosis in mice is bleomycin-induced lung fibrosis. This grant presents evidence that manipulation of the RAS may be useful in preventing bleomycin-induced injury and lung fibrosis. This proposal is to study mice with a genetic modification in ACE that eliminates the N-domain catalytic activity. These mice are called N-KO;they have reduced lung inflammation and fibrosis following bleomycin injury.
My first aim i s to study why this phenomenon occurs. My hypothesis is that the increased AcSDKP (an ACE substrate) concentration in the N-KO reduces inflammation because of a different inflammatory cytokine milieu and decreased oxidative damage. Increased AcSDKP concentration may also suppress TGF-?1/Smad signal transduction and decrease fibrosis.
The second aim i s to manipulate AcSDKP concentration and/or ACE inhibition as a means to reduce bleomycin-induced lung injury. By increasing AcSDKP concentration or by selective N-terminus blockage of ACE in wild type mice, reduced bleomycin-induced lung injury should be observed.
This aim will provide substantial preclinical characterization to enable a rationale for possible human clinical trials.

Public Health Relevance

In the US, pulmonary fibrosis is a serious medical problem affecting more than 200,000 patients and is responsible for over 40,000 deaths annually, according to the NHLBI. The general objective of this grant application is to increase our knowledge about how ACE functions and the roles of its substrates in the control of inflammation and fibrotic diseases. The outcome of the grant application should provide substantial preclinical characterization to enable a rationale to be developed for possible human clinical trials to treat lung disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL105036-02
Application #
8296527
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Colombini-Hatch, Sandra
Project Start
2011-06-15
Project End
2013-01-13
Budget Start
2012-06-15
Budget End
2013-01-13
Support Year
2
Fiscal Year
2012
Total Cost
$41,910
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Shen, Xiao Z; Okwan-Duodu, Derick; Blackwell, Wendell-Lamar et al. (2014) Myeloid expression of angiotensin-converting enzyme facilitates myeloid maturation and inhibits the development of myeloid-derived suppressor cells. Lab Invest 94:536-44
Ong, F S; Vakil, H; Xue, Y et al. (2013) The M694V mutation in Armenian-Americans: a 10-year retrospective study of MEFV mutation testing for familial Mediterranean fever at UCLA. Clin Genet 84:55-9
Grobe, Nadja; Weir, Nathan M; Leiva, Orly et al. (2013) Identification of prolyl carboxypeptidase as an alternative enzyme for processing of renal angiotensin II using mass spectrometry. Am J Physiol Cell Physiol 304:C945-53
Shen, Xiao Z; Ong, Frank S; Bernstein, Ellen A et al. (2012) Nontraditional roles of angiotensin-converting enzyme. Hypertension 59:763-8
Ong, Frank S; Deignan, Joshua L; Kuo, Jane Z et al. (2012) Clinical utility of pharmacogenetic biomarkers in cardiovascular therapeutics: a challenge for clinical implementation. Pharmacogenomics 13:465-75
Ong, Frank S; Lin, Chentao X; Campbell, Duncan J et al. (2012) Increased angiotensin II-induced hypertension and inflammatory cytokines in mice lacking angiotensin-converting enzyme N domain activity. Hypertension 59:283-90
Ong, Frank S; Grody, Wayne W; Deignan, Joshua L (2011) Privacy and data management in the era of massively parallel next-generation sequencing. Expert Rev Mol Diagn 11:457-9