Scleroderma or Systemic Sclerosis (SSc) is a disease of unknown etiology characterized by the excessive deposition of collagen and other connective tissue components in skin and multiple internal organs, prominent and often severe alterations in the microvasculature, and numerous humoral and cellular immunologic abnormalities. Although the mechanisms involved in the pathogenesis of SSc are not completely known, it is clear that cutaneous, visceral, and vascular fibrosis is responsible for the most severe clinical manifestations and the mortality of the disease. The overall objective of this application is to identify some of the molecular events that may be involved in the exaggerated production of collagen and in the microvascular abnormalities in SSc. Several novel areas of investigation have been identified during the previous funding period including the significant association of SSc with certain alleles of the gene encoding Allograft Inflammatory Factor 1 (AIF1), the demonstration of ATP 1 in inflammatory and endothelial cells in SSc affected microvasculature, the demonstration of a possible role of geranylgeranyl isoprenylation and of RhoA and protein kinase C8 (PKC8) in the upregulated expression of collagen genes in SSc, and the demonstration that statins exert potent inhibition of collagen gene expression. Based on these results, we propose to test the following hypotheses: (1) AIF1, a protein expressed in lymphocytes, macrophages and microvascular fibroproliferative lesions from SSc patients, plays an important role in the pathogenesis of the vascular abnormalities characteristic of the disease;(2) the excessive production of collagen in SSc involves abnormalities in non-Smad pathways including abnormalities in RhoA signaling, geranylgeranyl isoprenylation and in the activation of the PKC5 pathway. These abnormalities result in the activation of transcription factors which eventually stimulate the expression of regulatory elements in the collagen genes. To test these hypotheses, we will pursue the following Specific Aims:
Specific Aim 1 : Determination of the role of AIF1 in the pathogenesis of the vascular obliterative process in SSc and further characterization of the functional role of the protein.
Specific Aim 2 : Examination of alterations in non-Smad pathways of collagen gene expression regulation focusing on the identification of abnormalities in RhoA, geranylgeranyl, and PKC8-mediated steps of collagen gene expression regulation in SSc fibroblasts. It is expected that results from these studies will provide valuable clues towards the understanding of the pathogenesis of tissue fibrosis and of the prominent microvascular alterations in SSc and may open new avenues of investigation towards the development of therapeutic agents for this serious and incurable disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Tseng, Hung H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Thomas Jefferson University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Kumar, S; Singh, J; Rattan, S et al. (2017) Review article: pathogenesis and clinical manifestations of gastrointestinal involvement in systemic sclerosis. Aliment Pharmacol Ther 45:883-898
Wermuth, Peter J; Carney, Kellan R; Mendoza, Fabian A et al. (2017) Endothelial cell-specific activation of transforming growth factor-? signaling in mice induces cutaneous, visceral, and microvascular fibrosis. Lab Invest 97:806-818
Jimenez, Sergio A; Piera-Velazquez, Sonsoles (2016) Endothelial to mesenchymal transition (EndoMT) in the pathogenesis of Systemic Sclerosis-associated pulmonary fibrosis and pulmonary arterial hypertension. Myth or reality? Matrix Biol 51:26-36
Mendoza, Fabian A; Piera-Velazquez, Sonsoles; Farber, John L et al. (2016) Endothelial Cells Expressing Endothelial and Mesenchymal Cell Gene Products in Lung Tissue From Patients With Systemic Sclerosis-Associated Interstitial Lung Disease. Arthritis Rheumatol 68:210-7
Piera-Velazquez, Sonsoles; Mendoza, Fabian A; Jimenez, Sergio A (2016) Endothelial to Mesenchymal Transition (EndoMT) in the Pathogenesis of Human Fibrotic Diseases. J Clin Med 5:
Mendoza, Fabian A; Mansoor, Maryah; Jimenez, Sergio A (2016) Treatment of Rapidly Progressive Systemic Sclerosis: Current and Futures Perspectives. Expert Opin Orphan Drugs 4:31-47
Mendoza, F A; Bai, R; Kebede, A G et al. (2016) Severe eosinophilic fasciitis: comparison of treatment with d-penicillamine plus corticosteroids vs. corticosteroids alone. Scand J Rheumatol 45:129-34
Londin, Eric; Loher, Phillipe; Telonis, Aristeidis G et al. (2015) Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs. Proc Natl Acad Sci U S A 112:E1106-15
Piera-Velazquez, Sonsoles; Jimenez, Sergio A (2015) Role of cellular senescence and NOX4-mediated oxidative stress in systemic sclerosis pathogenesis. Curr Rheumatol Rep 17:473
Piera-Velazquez, Sonsoles; Makul, Alma; Jiménez, Sergio A (2015) Increased expression of NAPDH oxidase 4 in systemic sclerosis dermal fibroblasts: regulation by transforming growth factor ?. Arthritis Rheumatol 67:2749-58

Showing the most recent 10 out of 61 publications