Interstitial lung disease (ILD) is a major complication and the leading cause of mortality in scleroderma (SSc, systemic sclerosis). The morbidity and mortality rates in African American scleroderma patients are higher when compared with SSc patients of other races. The goal of this project is to fill gaps in knowledge of pathophysiologic links between African American race and SSc-ILD that may account for the racial differences in SSc-ILD outcomes, and potentially other rheumatic lung disease outcomes as well. In studies to date we identified a genetic variant in African American SSc patients that is likely to be responsible for the higher severity of SSc-ILD in African-Americans. In particular, we found that hepatocyte growth factor (HGF) receptor c-MET in lung fibroblasts from African American SSc-ILD patients contains the mutation D1398G that is not observed in white patients. Moreover, in cultured SSc lung fibroblasts from whites HGF downregulates the expression of extracellular matrix (ECM) proteins, whereas in fibroblasts from the African American SSc patients who have mutation D1398G, HGF does not exhibit this activity due to its inability to induce c-MET phosphorylation. Thus, our results suggest that the defective phosphorylation of HGF receptor in African American SSc lung fibroblasts is a direct consequence of the D1398G mutation. Our organizing hypotheses that drive this component project of the MCRC are that severity of SSc-ILD in African American patients is caused by a defect in the phosphorylation mechanisms of c-MET regulation of ECM proteins in lung, and that the D1398G variant of the c-MET gene is the source of this defect.
Specific Aim 1 will test the hypothesis that D1398G variant of c-MET gene is a somatic mutation that modulates the disease severity in SSc-ILD patients.
Specific Aim 2 will test the hypothesis that specific SNPs within the coding region of c-MET gene will be associated with D1398G variant of c-MET in SSc-ILD patients, thereby leading to a potential biomarker of SSc-ILD severity.
Specific Aim 3 will test the hypothesis that D1398G variant of c-MET gene is causally responsible for the defective HGF signaling in African American SSc patients. The combined results of these studies will enhance our understanding of the molecular mechanisms of SSc-ILD and ultimately may lead to the development of effective diagnostics, prognostics and therapies that will depend on and can be tailored to the patient s genotype.

Public Health Relevance

Interstitial lung disease (ILD) is a major complication and the leading cause of mortality in scleroderma (SSc, systemic sclerosis) with significantly higher morbidity and mortality rates in African American scleroderma patients. The studies described in the current proposal will be first in the field of scleroderma research to provide genetic and mechanistic evidence underpinning the known health disparities in African American SSc patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Comprehensive Center (P60)
Project #
1P60AR062755-01
Application #
8295198
Study Section
Special Emphasis Panel (ZAR1-KM (M1))
Project Start
2012-07-01
Project End
2017-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$316,011
Indirect Cost
$101,766
Name
Medical University of South Carolina
Department
Type
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Putterman, Chaim; Wu, Alan; Reiner-Benaim, Anat et al. (2016) SLE-key(®) rule-out serologic test for excluding the diagnosis of systemic lupus erythematosus: Developing the ImmunArray iCHIP(®). J Immunol Methods 429:1-6
Deng, Yun; Zhao, Jian; Sakurai, Daisuke et al. (2016) Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production. Ann Rheum Dis 75:2007-2013
Zhao, Jian; Giles, Brendan M; Taylor, Rhonda L et al. (2016) Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA. Ann Rheum Dis 75:242-52
Toci, Ashley L; Hyer, J Madison; Silver, Richard M et al. (2016) Systemic Sclerosis and Perceptions of Quality in Primary Care. Am J Med Sci 351:447-51
Wolf, Bethany J; Spainhour, John C; Arthur, John M et al. (2016) Development of Biomarker Models to Predict Outcomes in Lupus Nephritis. Arthritis Rheumatol 68:1955-63
Liu, Ke; Kurien, Biji T; Zimmerman, Sarah L et al. (2016) X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome. Arthritis Rheumatol 68:1290-300
Atanelishvili, Ilia; Shirai, Yuichiro; Akter, Tanjina et al. (2016) M10, a caspase cleavage product of the hepatocyte growth factor receptor, interacts with Smad2 and demonstrates antifibrotic properties in vitro and in vivo. Transl Res 170:99-111
Zhou, Zejun; Ding, Miao; Huang, Lei et al. (2016) Toll-like receptor-mediated immune responses in intestinal macrophages; implications for mucosal immunity and autoimmune diseases. Clin Immunol 173:81-86
Ramos, Paula S; Silver, Richard M; Feghali-Bostwick, Carol A (2015) Genetics of systemic sclerosis: recent advances. Curr Opin Rheumatol 27:521-9
Lu, Xiaoming; Zoller, Erin E; Weirauch, Matthew T et al. (2015) Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression. Am J Hum Genet 96:731-9

Showing the most recent 10 out of 58 publications