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Projects / Programmes source: ARIS

Investigating mechanisms leading to fibrosis development in systemic sclerosis

Research activity

Code Science Field Subfield
3.01.00  Medical sciences  Microbiology and immunology   

Code Science Field
B580  Biomedical sciences  Skeleton, muscle system, rheumatology locomotion 

Code Science Field
3.01  Medical and Health Sciences  Basic medicine 
Keywords
fibrosis, systemic sclerosis, inflammation, innate imunity, metabolism
Evaluation (rules)
source: COBISS
Researchers (1)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  28845  PhD Katja Lakota  Microbiology and immunology  Head  2018 - 2020  233 
Organisations (1)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0312  University Medical Centre Ljubljana  Ljubljana  5057272000  76,666 
Abstract
Chronic fibroproliferative process, which occurs as unresolved wound healing process and results in excess extracellular matrix deposition, is the basis for organ architecture and function damage in many diseases, one of them being systemic autoimmune rheumatic disease systemic sclerosis. Systemic sclerosis is autoimmune disease, with fibrosis as the hallmark, affecting skin and internal organs. While fibrosis of skin is the most visible in this disease, up to 40% of patients develop interstitial lung fibrosis, which is the leading cause of death in these patients. Innate immunity, inflammation and DNA damage play important role in wound healing process leading to fibroblast to myofibroblast differentiation and proliferation of these cells instead undergoing apoptosis. It was shown that perpetual stimulation of pattern recognition receptors (Toll like receptors) with endogenous molecules stimulate profibrotic response of resident stromal fibroblasts [1]. Opposing role was proposed for anti-inflammatory lipid mediators lipoxin A4 and resolvin D1 signaling trough ALX receptor, with major acute phase protein serum amyloid A connecting both signaling pathways [2]. The main fibrosis driving cell type - myofibroblasts are highly proliferating cells, producing extracellular matrix and thereby have profound changes in metabolism, which have not been investigated in details up to now. The overall objective of this project is to study crossroads between innate immunity receptors in fibroblasts preventing return of fibroblasts into quiescent state, resulting in possible novel targets for therapeutic intervention with emphasis on metabolic changes in myofibroblasts and to measure changes (dsDNA breaks, telomere length) in peripheral blood mononuclear cells as possible biomarker for DNA damage. The project aims to advance understanding of mechanisms preventing deactivation of extracellular matrix synthesis and thus leading to fibrosis development, forming basis for novel therapeutic approach as well as provide new biomarkers crucially needed for diagnosing/prognosis of this devastating disease. 1. Bhattacharyya S, Wang W, Morales-Nebreda L, Feng G, Wu M, et al. (2016) Tenascin-C drives persistence of organ fibrosis. Nat Commun 7: 11703. 2. Lakota K, Carns M, Podlusky S, Mrak-Poljsak K, Hinchcliff M, et al. (2015) Serum amyloid A is a marker for pulmonary involvement in systemic sclerosis. PLoS One 10: e0110820.
Significance for science
This research would for the first time unravel interplay between endogenous ligands of two receptors on fibroblasts, both shown to be importantly implicated in fibrosis, which could lead to novel therapeutic targets. Additionally, we plan for the first time to evaluate metabolism in miofibroblast as compared to fibroblasts and elucidate how changes in metabolism contribute to pathologic phenotype of fibroblast. Results will establish novel strategy -how to reverse metabolic changes in order to treat fibrotic process. Last but not least, we will clarify for the first time if measurement of DNA damage and telomere length is useful as possible novel biomarker associated with diagnosis/prognosis of SSc, to help clinicians in their decision for therapy.
Significance for the country
This research would for the first time unravel interplay between endogenous ligands of two receptors on fibroblasts, both shown to be importantly implicated in fibrosis, which could lead to novel therapeutic targets. Additionally, we plan for the first time to evaluate metabolism in miofibroblast as compared to fibroblasts and elucidate how changes in metabolism contribute to pathologic phenotype of fibroblast. Results will establish novel strategy -how to reverse metabolic changes in order to treat fibrotic process. Last but not least, we will clarify for the first time if measurement of DNA damage and telomere length is useful as possible novel biomarker associated with diagnosis/prognosis of SSc, to help clinicians in their decision for therapy.
Most important scientific results Interim report, final report
Most important socioeconomically and culturally relevant results Final report
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