Systemic sclerosis (SSc; Scleroderma) is a connective tissue disease of unknown etiology that is associated with significant morbidity and mortality. It has long been presumed that SSc likely results from environmental triggers, although these environmental insults have not been identified. The gold standard for assessing the role of environmental and inherited genetic effects on the development of a disease is the study of twins. A cross sectional study of twins with SSc we conducted several years ago showed a comparable concordance for disease of approximately 5% in monozygotic (MZ) and dizygotic (DZ) twins. Published research on familial cases of SSc, in conjunction with findings from our twin study, suggests that SSc likely develops in individuals with a genetically susceptible background upon exposure to appropriate environmental triggers or via acquired genetic changes. We therefore propose in specific aim 1 to identify environmental factors that may associate with SSc using the twin cohort and a large cohort of SSc patients and matched controls. Since epigenetic regulation has emerged as an important mechanism mediating gene expression and the manifestation of a disease phenotype, specific aim 2 is designed to compare the DNA methylation profile of twins participating in our study. Lastly, we will explore the effect of environmental factors on DNA methylation in specific aim 3. Our findings will significantly advance our understanding of disease pathogenesis in SSc, provide novel insights into epigenetic mechanisms underlying the disease, and identify a causal relationship between environmental factors and altered DNA methylation. Our findings will propel progress in the field and provide new avenues for research for mentees to facilitate their research and allow them to establish their own independent research programs. These mentees will be integral participants in the PI's program throughout the award period. The PI will mentor young physician scientists in the assessment of SSc in patients and the absence of disease in healthy twins, the evaluation of Raynaud phenomenon, obtaining informed consent, administration of questionnaire to patients and controls, use of clinical samples, the examination of DNA methylation profiles, the application of the University of Pittsburgh Scleroderma SerumBank and matching clinical Database to their research projects, and the analysis of environmental factors on DNA methylation. Together, these approaches will train the mentees in epidemiology, identification of risk factors, environmental medicine, and clinical epigenetics. The mentoring goals of this application also include mentoring young physician scientists in patient-oriented research, grantsmanship, manuscript writing, responsible conduct of research, and career development. The PI's reputation as an excellent mentor coupled with the collaborative and supportive environment at the University of Pittsburgh, the resources available at the institution and via the CTSI, and the resources of the Scleroderma Center of Pittsburgh, provide the perfect environment for attracting and training successful physician scientists. Our success will provide a pipeline of clinical investigators to continue the mission of treating patients and identifying te cause and cure for Scleroderma and related diseases.

Public Health Relevance

Systemic sclerosis (SSc) is a disease with no known cause or cure. We had reported that concordance for SSc in twins is lower than that reported for other rheumatic diseases. This suggests that SSc develops in individuals who are genetically susceptible and develop the disease once they are exposed to factors such as environmental factors that can induce modifications to the DNA known as epigenetic changes. We propose to identify environmental risk factors associated with SSc. We also propose to examine epigenetic changes of DNA that may be responsible for identical twins being discordant for disease and establish a causal relationship between environmental factors and these changes in DNA that may lead to SSc. Through this award, the PI will also mentor young physician scientists in epidemiology, environmental medicine and clinical epigenetics to ensure a pipeline of future independent clinician scientists with research interests focused on Scleroderma and related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24AR060297-06
Application #
9189679
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Mancini, Marie
Project Start
2013-10-01
Project End
2017-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
Fan, Ming-Hui; Zhu, Qiang; Li, Hui-Hua et al. (2016) Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice. J Biol Chem 291:8070-89
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
Bhattacharyya, Swati; Wang, Wenxia; Morales-Nebreda, Luisa et al. (2016) Tenascin-C drives persistence of organ fibrosis. Nat Commun 7:11703
Ahluwalia, Neil; Grasberger, Paula E; Mugo, Brian M et al. (2016) Fibrogenic Lung Injury Induces Non-Cell-Autonomous Fibroblast Invasion. Am J Respir Cell Mol Biol 54:831-42
Ramos, Paula S; Silver, Richard M; Feghali-Bostwick, Carol A (2015) Genetics of systemic sclerosis: recent advances. Curr Opin Rheumatol 27:521-9
Torok, Kathryn S; Kurzinski, Katherine; Kelsey, Christina et al. (2015) Peripheral blood cytokine and chemokine profiles in juvenile localized scleroderma: T-helper cell-associated cytokine profiles. Semin Arthritis Rheum 45:284-93
Roach, Katy M; Feghali-Bostwick, Carol A; Amrani, Yassine et al. (2015) Lipoxin A4 Attenuates Constitutive and TGF-β1-Dependent Profibrotic Activity in Human Lung Myofibroblasts. J Immunol 195:2852-60
Su, Yunyun; Nishimoto, Tetsuya; Feghali-Bostwick, Carol (2015) IGFBP-5 Promotes Fibrosis Independently of Its Translocation to the Nucleus and Its Interaction with Nucleolin and IGF. PLoS One 10:e0130546
Nishimoto, Tetsuya; Mlakar, Logan; Takihara, Takahisa et al. (2015) An endostatin-derived peptide orally exerts anti-fibrotic activity in a murine pulmonary fibrosis model. Int Immunopharmacol 28:1102-5
Fan, Ming-Hui; Feghali-Bostwick, Carol A; Silver, Richard M (2014) Update on scleroderma-associated interstitial lung disease. Curr Opin Rheumatol 26:630-6

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