Multi-level Molecular Profiling of High Acute Stress: a Clinical Study

Overview

Although it is well known that stress plays an important role in the development of neuropsychiatric diseases, the precise role and molecular effects of stress have only been poorly understood. For example, autophagy is essential for energy and cellular homeostasis through protein catabolism, and dysregulation results in compromised proteostasis, stress-coping behavior, and excessive secretion of signaling molecules and inflammatory factors. Therefore, the aim of the project is to analyze the clinical effects of a bungee jump resembling an acute stress event in correlation to autophagy and other underlying, multi-level molecular profiling. Specifically, it is planned to perform multi-level molecular profiling and sleep analysis in a cohort of healthy male individuals before, during, and after a bungee jump compared to a control cohort of healthy males not undergoing a stress event. The resulting findings will advance the role of autophagy during the stress response and hence in the development of psychiatric disorders, and possibly investigate alternative treatment venues on a molecular level, and finally contribute to a better clinical outcome.

Although it is well known that stress plays an important role in the development of neuropsychiatric diseases, the molecular effects of stress have only been poorly understood. So far it is known that stress leads to an activation of the stress hormone axis followed by an increased release of the stress hormone and glucocorticoid cortisol. Glucocorticoids bind to glucocorticoid receptors that initiate a cellular signal cascade. However, it can be assumed that other factors are involved but a profound understanding of the stress response at the molecular level has not yet been performed yet. Using a so-called "multi-omics approach" it is possible to determine changes in a large number of molecular groups, such as proteins or lipids to research the underlying mechanisms of diseases. While multi-omics analyzes have already helped gain elementary knowledge in a large number of somatic diseases, the molecular effects of acute stress have not been addressed yet. This will be the primary focus of this study. To achieve this an acute, concise stress reaction closely resembling a genuine stress response is desired. In previous studies, it was shown that bungee jumping triggers such a short, intense stress reaction and the corresponding activation of the stress hormone axis. To achieve this a cohort of 25-30 healthy male individuals who undergo a bungee jump resembling an acute stress event will be compared to a cohort of 10-20 healthy males who undergo the same experimental design without undertaking a bungee jump or other stress intervention. At different time points (baseline, shortly before and after the intervention, at multiple time points during the intervention as well as around one week follow up after the intervention) serval psychometrical questionnaires will be gathered and blood will be collected. A dexamethasone inhibition test will be performed before the stress intervention. Sleep quality will be additionally assessed during the entire course of the study by actigraphy. On selected days blood will be collected. Following, autophagy activity will be assessed by Western Blot analysis, and mass spectrometry-based proteomics, phosphoproteomics, metabolomics, and lipidomics will be performed. Bioinformatic analysis, statistical evaluation, quality control, and in silico pathway analyses will then specifically identify factors and cascades of relevance. The aim of the project is to analyze the clinical effects of an acute stress event in correlation to the underlying, multi-level molecular profiling. Longitudinal multi-omic profiling including proteome, metabolome, lipidome, and epigenetic changes will reveal time-series analysis of thousands of molecular changes and an orchestrated composition of autophagy depended signaling. The resulting findings will advance the role of autophagy in the development of psychiatric disorders, and possibly investigate alternative treatment venues on a molecular level, and finally contribute to a better clinical outcome.