NFATc1 and CRAC channel signaling in acute pancreatitis

by Anna Lena Weber
Doctoral thesis
Date of Examination:2025-03-13
Date of issue:2025-07-04
Advisor:Prof. Dr. Volker Ellenrieder
Referee:Prof. Dr. Volker Ellenrieder
Referee:Prof. Dr. Jürgen Wienands
Persistent Address: http://dx.doi.org/10.53846/goediss-11356

 

 

Files in this item

Name:20250114_Thesis-final.pdf
Size:4.02Mb
Format:PDF

The following license files are associated with this item:

Abstract

English

Abstract Acute pancreatitis (AP) is an inflammatory disorder of the pancreas which is associated with an overall mortality of up to 5%. As its prevalence rises, the burden on the healthcare system and patients becomes increasingly more substantial, especially considering that no curative treatments are currently available. The triggers of AP are very diverse, including bile acid reflux, abuse of alcohol, and cigarette smoking. Diverging disease causes complicate the development of uniform therapy approaches and research into the molecular pathology. However, disruption of the calcium (Ca2+) homeostasis in the exocrine pancreatic acinar cells (PACs) has been identified as a central and mostly cause-independent pathological driver. Ca2+ hereby accumulates in the cytoplasm of PACs and drives acinar cell damage by disrupting mitochondrial function, blocking ATP production, and ultimately resulting in cell death. As such, targeting Ca2+ signaling has emerged as an attractive therapeutic target, with the Ca2+ channel inhibitor CM4620 currently enrolled in phase II clinical trials. Similarly, investigating the role of Ca2+ downstream effector proteins is becoming increasingly more interesting in hopes of identifying targetable proteins in the transcriptional regulation of Ca2+-originated signaling pathways. Hereby, we investigated the role of the Ca2+ activated transcription factor nuclear factor of activated T-Cells c1 (NFATc1). NFATc1 regulates diseases severity by driving cytokine production with subsequent recruitment of immune cells, as well as acinar cell damage by regulation of Ca2+ influx and mitochondrial fitness. Notably, we demonstrate a novel regulatory relationship between the entry of extracellular Ca2+ and NFATc1 activity. Activation of NFATc1 requires an influx of Ca2+ and can be blocked by inhibiting Ca2+ influx. We demonstrate that in addition, NFATc1 regulates the expression of STIM1, a Ca2+ channel component, thereby facilitating Ca2+ entry and self-activation. This regulatory relationship promotes a pathological positive feedback loop in the context of AP by driving acinar cell damage and death through increased intracellular Ca2+ signaling activity. We explore the genetic deletion of NFATc1, as well as the use of CM4620 in order to inhibit AP progression driven by the aforementioned feedback loop and establish NFATc1 facilitated Ca2+ signaling and acinar cell damage as a novel central driver of AP pathogenesis.
Keywords: Acute Pancreatitis; Calcium Signaling; NFATc1; SOCE
 
Statistik