SP14

Principal Investigator: Otmar Huber (Institute for Biochemistry II, Jena University Hospital)

Pauline Förster (PhD): The role of Nit1 in aging-associated stress response

In this project we want to identify effectors and pathways that are regulated by Nit1 and how these effectors affect aging-associated stress responses. Using a mass spectrometry-based approach to compare cells with a stable shRNA-mediated knock-down of Nit1 with scrambled shRNA-treated control cells, we want to screen for differentially regulated proteins. After bioinformatic analysis and verification of candidates we will study the role of Nit1 in the regulation of candidates specifically in the context of our previously observed crosstalk with FOXO3a and b-catenin signaling and how Nit-dependent regulation of these factors may affect senescence and aging.

Dhanalakshmi Jothi (PhD): The role of Nit1 in Wnt/ß-catenin - FOXO signalling in stress response and ageing

Ageing-associated changes in tissue homeostasis are a consequence of multiple molecular and cellular changes induced by alterations of signalling and metabolic pathways and accumulation of damaged molecules due to impaired repair mechanisms. We recently identified Nit1 as a new binding partner of b-catenin and repressor of the canonical Wnt-pathway disrupting the b-catenin/TCF-complex. Stress conditions were reported to redirect b-catenin from TCF to FOXO3a thereby activating FOXO3a transcriptional activity. Our results indicate that Nit1 is differentially regulated in stress responses and thereby could contribute to this effect. Interestingly, Nit1 has a second role as a metabolite repair enzyme acting as a dGSH (deamino-glutathione)-hydrolase. dGSH is generated as a side product of transaminase reactions. We here want to assess this dual role of Nit1 in stress response and investigate which posttranslational modifications modulate this activity during ageing and senescence.