Project Details
Projekt
Pyroptotic cell death in excessively stressed human periodontal ligament cells - a potential mechanism for hyperinflammatory responses?
Applicant
Professor Dr. Collin Jacobs
Subject Area
Dentistry, Oral Surgery
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 530363282
The application of mechanical forces during orthodontic treatment triggers an aseptic transient inflammatory response in cells of the periodontal ligament (PdL), which is located between the tooth and the alveolar bone. Hyperinflammatory PdL mechanoresponses followed by impaired downstream processes, including tissue and bone remodeling, increase the probabilities of orthodontic risks such as tooth root regretion or tooth loss. Critically, the underlying mechanisms and thus potential targets for the development of clinical intervention strategies have not been explored in sufficient detail. Initially characterized as a mechanism of pathogen defense, inflammasome activation and subsequent pyroptosis have also recently been demonstrated as part of the PdL mechanoresponse. Based on recent preliminary studies of my research group, we hypothesize that inflammasome activation and pyroptotic cell death may underlie excessive pro-inflammatory mechanoresponses. Moreover, preliminary results suggesting the growth differentiation factor GDF15 as potential modulator in inflammasome/pyroptosis-related hyperinflammation. GDF15 is strongly associated with the regulation of inflammatory processes, particularly including the mechanoresponse of PdL cells, shown by own studies. By applying a comprehensive setup of in vitro and in vivo analysis, we aim to (1) determine the role of inflammasome activation and pyroptosis in hyperinflammatory PdL fibroblast mechanoresponses and (2) identify the specific role of GDF15 in this regard. We will focus specifically on the effects of obesity-induced hyperlipidemia, identified by our own studies to promote mechano-hyperinflammation. Applied analysis will include in particular high-throughput sequencing-based RNA profiling, proteomic and secretomic analyses, morphological studies, and functional co-culture validations. The role of GDF15 will be addressed using a specific gene knockout. Overall, the study will significantly contribute to the elucidation of regulatory mechanisms in hyperinflammatory mechanoresponses and thus provide new avenues for future personalized therapeutic approaches. Due to the diverse immunoregulatory functions of GDF15 in a variety of tissues, this study will uncover new multidisciplinary insights into the functionality of GDF15.
DFG Programme
Research Grants
