Detailseite
Projekt
Involvement of ALADIN in adrenal cell function and hormone and response
Antragstellerin
Professorin Dr. Angela Hübner, Ph.D.
Fachliche Zuordnung
Endokrinologie, Diabetologie, Metabolismus
Förderung
Förderung von 2011 bis 2018
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 189897882
ALADIN, encoded by the AAAS gene, is a component of the nuclear pore complex. ALADIN is dysfunctional in triple A syndrome, which is associated with severe adrenal insufficiency. The diversity of symptoms observed in patients suggests that different functional cellular pathways are involved in the pathogenesis of the disorder. In the first funding period we characterized the impairment of the adrenal steroidogenic pathway and adrenomedullary function in three different adrenal models. Our findings indicate that there is an ALADIN dependent crosstalk between adrenocortical and medulla cells. We now plan to identify potential signaling molecules, which are necessary for this crosstalk. Since we observed no rescue of steroidogenesis after downregulation and recovery of ALADIN in the human adrenal cell line NCI-H295R we plan to study epigenetic changes in these cells, which we hypothesize are the cause for this observation. Furthermore we will examine p38MAPK alterations as one aspect of stress-induced premature senescence. We will study the involvement of ALADIN in Shh regulation and in proliferation, cell cycle regulation and apoptosis. We will investigate mechanisms by which ALADIN protects the adrenal cells from reactive oxygen species and will test the potential of antioxidative treatment. After proof of principle in cell culture and our mouse models we prospectively plan a multicenter clinical trial in our world-largest cohort of triple A syndrome patients.
DFG-Verfahren
Klinische Forschungsgruppen
