Ricerc@Sapienza

Hutchinson Gilford Progeria Syndrome (HGPS) is a rare genetic disorder which is characterized by mutations in lamin A, resulting in premature aging in children, severe cardiovascular complications and early death. A full understanding of HGPS is not yet available and hence therapeutic strategies are far from being optimized. However, it is well established that HGPS lamin A mutations cause nuclear fragility, a pivotal component of the disease phenotype. This aspect in turn points to the involvement in HGPS of the endosomal sorting complex required for transport (ESCRT), a machinery controlling nuclear integrity. Indeed, ESCRT members CHMP2 and CHMP7 have been associated with nuclear envelope sealing and linked with HGPS. We have experimental evidence of a new putative ESCRT associated factor named AKTIP, highly similar to ESCRT protein TSG101. AKTIP is enriched at the nuclear envelope and its localization is controlled by lamin A and affected by progeroid lamin A mutations.
The objectives of this proposal are: i) Deepen the understanding of HGPS pathomechanisms and ii) Explore new paths for therapy of HGPS, by studying the ESCRT complex mechanistically, genetically and as a therapeutic tool. To achieve my goals I will: i) Characterize by super resolution microscopy and biochemistry nuclear envelope and ESCRTs in wild type and progeroid conditions and ii) Produce lentivectors encoding ESCRT components as gene therapy approach to rescue HGPS nuclear defects.
In summary, through the outlined research I expect: i) To clarify mechanical aspects of HGPS; ii) To produce a gene therapy tool for progeroid nuclei repair; iii) Obtain new insights on ESCRTs at the nuclear envelope.