NUEVOS AGENTES PARA MODULAR LA ACTIVIDAD FIBRÓTICA EN FIBROBLATSOS
Crohn's Disease (CD) is a form of inflammatory bowel disease characterized by notable heterogeneity, which has led to the establishment of a classification into three main phenotypes: inflammatory, fistulizing and stenosing. The stenosing phenotype presents a genetic predisposition, which impli...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/418507 |
| Acceso en línea: | http://hdl.handle.net/10261/418507 |
| Access Level: | acceso abierto |
| Palabra clave: | Crohn's Disease (CD) Pharmacology http://metadata.un.org/sdg/9 http://metadata.un.org/sdg/12 http://metadata.un.org/sdg/3 http://metadata.un.org/sdg/17 Ensure healthy lives and promote well-being for all at all ages Build resilient infrastructure, promote inclusive and sustainable industrialization and foster innovation Ensure sustainable consumption and production patterns Strengthen the means of implementation and revitalize the Global Partnership for Sustainable Development |
| Sumario: | Crohn's Disease (CD) is a form of inflammatory bowel disease characterized by notable heterogeneity, which has led to the establishment of a classification into three main phenotypes: inflammatory, fistulizing and stenosing. The stenosing phenotype presents a genetic predisposition, which implies an abnormal process of repair of intestinal injury, resulting in intestinal fibrosis. Fibrosis is a pathological process marked by the excessive accumulation of extracellular matrix and the formation of scar tissue, largely mediated by the activation of fibroblasts and their differentiation towards myofibroblasts. Transforming Growth Factor Beta (TGF-β) is a key cytokine that plays a crucial role in regulating these processes. Yes-Associated Protein (YAP) and Transcriptional Coactivator with PDZ-binding motif (TAZ) are related mechanosensory proteins that bind Smad transcription factors, the canonical mediators of profibrotic TGF-β responses. Currently, there is no definitive cure for intestinal fibrosis, although various avenues of research are ongoing. This project investigates the inhibition of YAP, using the drug Verteporfin (V) conjugated with specific peptides targeting fibroblast membrane receptors, Internalizing RGD (iRGD) (which binds to ITαvβ5) and CPP (which binds to Fibroblast Activating Protein (FAP)), as a targeted antifibrotic strategy, in cells stimulated with TGF-β. The effect of these peptide-drug conjugates (referred to here simply as conjugates), iRGD-V and CPP-V, on cell migration and the expression of various fibrogenic factors was evaluated: Vascular Endothelial Growth Factor (VEGF), Connective Tissue Growth Factor (CTGF) and FAP. The data obtained from in vitro treatment with iRGD-V and CPP-V conjugates highlight their potential in modulating stimulated fibroblast migration and decreasing fibrotic activity, with CPP-V showing greater efficacy to unstimulated fibroblasts. |
|---|