The investigation of the GIT2-RXFP3 synergistic system and its potential role in aging and age-related disorders

Most treatments for age-related disorders have been symptomatic, or target one aspect at a time, we hypothesize however that to combat these disorders at a global early level, we need to prevent these pathologies at a network level. This could be facilitated via the identification of a network-regulating master controller proteins whose modulation would thus possess multidimensional effects, termed ‘keystone’. One such aging keystone has recently been discovered, G protein-coupled receptor (GPCR) kinase interacting protein 2 (GIT2), a scaffolding protein and thus unfortunately not a canonical drug target. Our recent work however has demonstrated that G protein-coupled receptors (GPCRs) can have transcriptional control of protein expression. As such, a GPCR-based control of GIT2 expression/functionality may be an important mechanism to therapeutically control the aging process. In this dissertation, we will discuss the discovery of one such a receptor, Relaxin family peptide 3 receptor (RXFP3). We have discovered that these two proteins activate different aspects of DNA damage response and repair. In addition, they have the ability to function together and facilitate these processes. DNA damage has been classified as one of the most important hallmarks of aging, as such suggesting that if we can compel RXFP3 to engage a GIT2-dependent signaling pathway, we could potentially ameliorate multiple pathologies associated with diverse age-related disorders. Through the combined use of proteomics, interactomics and bioinformatic analysis, we were able to establish the role of the GIT2-RXFP3 system and already identify a potential GIT2-biased ligand.

Jaar van publicatie:2020

Trefwoorden:Doctoral thesis

Toegankelijkheid:Open