This PhD project is framed within the study of telomeropathies, a group of rare diseases characterized by a premature or excessive shortening of telomeres, nucleoprotein structures located at the ends of linear chromosomes that are responsible for protecting them from degradation or fusion with other chromosomes. Mutations in the genes involved in the assembly or maintenance of telomeres are responsible for this type of pathologies, including idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita (DC) and aplastic anemia (AA), all of which have high mortality rates and no curative treatments available. Two peptides derived from the dyskerin protein have been previously described to reverse some of the biological effects observed in patient cells, GSE24.2 and GSE4. The main objective of this project is to identify new peptides derived from the dyskerin protein with greater therapeutic activity than those previously described. To this end, the following specific objectives have been established:

1. To design new peptides derived from the dyskerin protein in collaboration with medicinal chemistry experts.
2. To evaluate their activity on biological processes related to telomeropathies, such as telomerase activity, response to DNA damage, oxidative stress levels, expression of proinflammatory molecules and the processes of apoptosis and cellular senescence. These assays will initially be performed in two cell lines: rat type II alveolar cells (RLE6TN) and human skin keratinocytes (HaCaT), using lentiviral vectors to express the peptides.
3. Explore different delivery mechanisms: since the use of lentiviruses requires complex gene therapy protocols, we will evaluate whether the peptides can enter cells by passive diffusion, endocytosis or through vehicles such as liposomes or nanoparticles, including pulmonary surfactant-based nanoparticles in the case of IPF.
4. Elucidate the molecular mechanism of action of the selected peptide through interaction studies and massive RNA sequencing to identify possible targets and molecular pathways altered by the peptide.
5. Validate the results in patient-derived cells, using fibroblasts derived from IPF patient biopsies, in collaboration with Dr. Maria Molina's group at Hospital de Bellvitge.

This project has a strong translational profile, as it aims to develop new therapies for diseases that currently have no curative treatment, contributing significantly to scientific progress and improving the quality of life of patients.