Ricerc@Sapienza

Hutchinson-Gilford Progeria Syndrome (HGPS, OMIM #177670) is a rare genetic disorder characterized by mutations in the nuclear protein lamin A. Mutations result in premature aging (progeria), severe cardiovascular complications and early death. A full understanding of HGPS is not yet available and therapeutic strategies are far from being optimized. It is established that HGPS mutations cause nuclear fragility and telomeric defects. However, the understanding of the interplay between telomeric defects and nuclear fragility is in its infancy. Along with this, the implication of the ESCRT (endosomal sorting complexes required for transport) machinery, which controls nuclear fragility, is yet unexplored in HGPS and other telomeric disorders, and also in telomere biology. We have experimental evidence that a factor named AKTIP controls telomere biology, is enriched at the nuclear border interacting with lamin A, is associated with ESCRTs and affected by HGPS mutations. In this project I want to build on the link between the nuclear border, ESCRTs and telomeres, highlighted by AKTIP, with the aims of deepening the understanding of the interaction between AKTIP, ESCRTs and telomeres, assessing the relationships between ESCRTs and telomeres in HGPS and explore new paths for therapy of HGPS, by evaluating the ESCRT complex as a therapeutic tool. To achieve these aims I will characterize by super resolution microscopy and biochemistry nuclear border, telomeres and ESCRTs in wild type and HGPS conditions. I will screen for ESCRT mutations patient samples with progeroid phenotype and produce vectors encoding ESCRT components as gene therapy approach to rescue HGPS nuclear fragility.