Integrative Multi-Omics Approach in Vascular Ehlers–Danlos Syndrome: Further Insights into the Disease Mechanisms by Proteomic Analysis of Patient Dermal Fibroblasts
<b>Background</b>: Dominant mutations in <i>COL3A1</i> are known to cause vascular Ehlers–Danlos syndrome (vEDS) by impairing extracellular matrix (ECM) homeostasis. This disruption leads to the fragility of soft connective tissues and a significantly increased risk of life-t...
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2024-11-01
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| author | Nicola Chiarelli Valeria Cinquina Nicoletta Zoppi Valeria Bertini Marianna Maddaluno Chiara De Leonibus Carmine Settembre Marina Venturini Marina Colombi Marco Ritelli |
| author_facet | Nicola Chiarelli Valeria Cinquina Nicoletta Zoppi Valeria Bertini Marianna Maddaluno Chiara De Leonibus Carmine Settembre Marina Venturini Marina Colombi Marco Ritelli |
| author_sort | Nicola Chiarelli |
| collection | DOAJ |
| description | <b>Background</b>: Dominant mutations in <i>COL3A1</i> are known to cause vascular Ehlers–Danlos syndrome (vEDS) by impairing extracellular matrix (ECM) homeostasis. This disruption leads to the fragility of soft connective tissues and a significantly increased risk of life-threatening arterial and organ ruptures. Currently, treatments for vEDS are primarily symptomatic, largely due to a limited understanding of its underlying pathobiology and molecular mechanisms. <b>Methods</b>: In this study, we conducted a comprehensive analysis of the intracellular proteome of vEDS fibroblasts, integrating these findings with our previous transcriptome results to identify key molecular pathways that drive the disease. Additionally, we explored the therapeutic potential of inhibiting miR-29b-3p as a proof of concept. <b>Results</b>: Our integrative multi-omics analysis revealed complex pathological networks, emphasizing the critical role of miRNAs, particularly miR-29b-3p, in impairing ECM organization, autophagy, and cellular stress responses, all of which contribute to the pathogenesis of vEDS. Notably, the inhibition of miR-29b-3p in vEDS fibroblasts resulted in the upregulation of several differentially expressed target genes involved in these critical processes, as well as increased protein expression of essential ECM components, such as collagen types V and I. These changes suggest potential therapeutic benefits aimed at improving ECM integrity and restoring intracellular homeostasis. <b>Conclusions</b>: Overall, our findings advance our understanding of the complex biological mechanisms driving vEDS and lay a solid foundation for future research focused on developing targeted and effective treatment strategies for this life-threatening disorder. |
| format | Article |
| id | doaj-art-9faa19e37a2c4c20a799889b18fb31ef |
| institution | Kabale University |
| issn | 2227-9059 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj-art-9faa19e37a2c4c20a799889b18fb31ef2024-12-27T14:12:42ZengMDPI AGBiomedicines2227-90592024-11-011212274910.3390/biomedicines12122749Integrative Multi-Omics Approach in Vascular Ehlers–Danlos Syndrome: Further Insights into the Disease Mechanisms by Proteomic Analysis of Patient Dermal FibroblastsNicola Chiarelli0Valeria Cinquina1Nicoletta Zoppi2Valeria Bertini3Marianna Maddaluno4Chiara De Leonibus5Carmine Settembre6Marina Venturini7Marina Colombi8Marco Ritelli9Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalyDivision of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalyDivision of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalyDivision of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalyTelethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, ItalyTelethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, ItalyTelethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, ItalyDivision of Dermatology, Department of Clinical and Experimental Sciences, ASST Spedali Civili and University of Brescia, 25123 Brescia, ItalyDivision of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalyDivision of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy<b>Background</b>: Dominant mutations in <i>COL3A1</i> are known to cause vascular Ehlers–Danlos syndrome (vEDS) by impairing extracellular matrix (ECM) homeostasis. This disruption leads to the fragility of soft connective tissues and a significantly increased risk of life-threatening arterial and organ ruptures. Currently, treatments for vEDS are primarily symptomatic, largely due to a limited understanding of its underlying pathobiology and molecular mechanisms. <b>Methods</b>: In this study, we conducted a comprehensive analysis of the intracellular proteome of vEDS fibroblasts, integrating these findings with our previous transcriptome results to identify key molecular pathways that drive the disease. Additionally, we explored the therapeutic potential of inhibiting miR-29b-3p as a proof of concept. <b>Results</b>: Our integrative multi-omics analysis revealed complex pathological networks, emphasizing the critical role of miRNAs, particularly miR-29b-3p, in impairing ECM organization, autophagy, and cellular stress responses, all of which contribute to the pathogenesis of vEDS. Notably, the inhibition of miR-29b-3p in vEDS fibroblasts resulted in the upregulation of several differentially expressed target genes involved in these critical processes, as well as increased protein expression of essential ECM components, such as collagen types V and I. These changes suggest potential therapeutic benefits aimed at improving ECM integrity and restoring intracellular homeostasis. <b>Conclusions</b>: Overall, our findings advance our understanding of the complex biological mechanisms driving vEDS and lay a solid foundation for future research focused on developing targeted and effective treatment strategies for this life-threatening disorder.https://www.mdpi.com/2227-9059/12/12/2749extracellular matrixcollagen type Icollagen type VmiR-29bmulti-omics approachproteome |
| spellingShingle | Nicola Chiarelli Valeria Cinquina Nicoletta Zoppi Valeria Bertini Marianna Maddaluno Chiara De Leonibus Carmine Settembre Marina Venturini Marina Colombi Marco Ritelli Integrative Multi-Omics Approach in Vascular Ehlers–Danlos Syndrome: Further Insights into the Disease Mechanisms by Proteomic Analysis of Patient Dermal Fibroblasts Biomedicines extracellular matrix collagen type I collagen type V miR-29b multi-omics approach proteome |
| title | Integrative Multi-Omics Approach in Vascular Ehlers–Danlos Syndrome: Further Insights into the Disease Mechanisms by Proteomic Analysis of Patient Dermal Fibroblasts |
| title_full | Integrative Multi-Omics Approach in Vascular Ehlers–Danlos Syndrome: Further Insights into the Disease Mechanisms by Proteomic Analysis of Patient Dermal Fibroblasts |
| title_fullStr | Integrative Multi-Omics Approach in Vascular Ehlers–Danlos Syndrome: Further Insights into the Disease Mechanisms by Proteomic Analysis of Patient Dermal Fibroblasts |
| title_full_unstemmed | Integrative Multi-Omics Approach in Vascular Ehlers–Danlos Syndrome: Further Insights into the Disease Mechanisms by Proteomic Analysis of Patient Dermal Fibroblasts |
| title_short | Integrative Multi-Omics Approach in Vascular Ehlers–Danlos Syndrome: Further Insights into the Disease Mechanisms by Proteomic Analysis of Patient Dermal Fibroblasts |
| title_sort | integrative multi omics approach in vascular ehlers danlos syndrome further insights into the disease mechanisms by proteomic analysis of patient dermal fibroblasts |
| topic | extracellular matrix collagen type I collagen type V miR-29b multi-omics approach proteome |
| url | https://www.mdpi.com/2227-9059/12/12/2749 |
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