KFO 342 - Coordination Funds

Basic data for this project

Description

Systemic inflammation may develop in response to non-infectious stimuli or upon infection with a pathogen. It has become evident, that an in-depth understanding of the stimulus- and patient-specific molecular pathophysiological pathways, defining the specific patient endotype, is required to apply a specific therapeutic approach to a stratified patient cohort. Likewise, it has to be acknowledged that not all patients presenting with the same clinical phenotype. The interindividual differences among patients and the multimodal causes of systemic inflammation certainly represent an explanation as to why these prior causal treatment approaches have not proven effective for unstratified patient collectives so far. A deeper understanding of the molecular mechanisms governing success or failure of certain treatment options will be key to successfully identify specific patient populations and to develop and establish individualized therapy approaches. The central goal of the first funding period was the identification and investigation of relevant molecular, immunological, and cellular pathways involved in organ injury during systemic inflammation and sepsis, and thus the identification and investigation of therapeutic treatment strategies. In many instances we have succeeded with this mission and, for example, revealed novel extrinsic and endogenous molecular mechanisms providing protection against acute kidney injury elicited by systemic inflammation, identified molecular pathways governing the immune response in the lung, and demonstrated that distinct molecular switches in monocytes and macrophages exist that determine the physiological resolution of inflammation or the persistence of immune hypo-responsiveness in the later stages following systemic inflammation. In the second funding period of the CRU342, we stand by our original concept focusing on the overarching aim to bridge basic science and clinical research to bring translational research to the next level. We will generate a reliable basis for future trials using individualized therapy approaches for the treatment of systemic inflammation and organ dysfunction. This can only be achieved by focusing research efforts on the investigation of disease/syndrome-specific endotypes and specific phenotypes. This involves the identification of patient cohorts based on their specific endo- and phenotype that are specifically treated with an agent that targets a signaling pathway that is predominant in this subpopulation. Our approach also involves the clinical verification and validation of identified treatment targets in clinical pilot studies as well as reverse translation of hypothesis-generating observations obtained from clinical research during the first funding period as new explorative research objectives for basic science projects. This involves the identification of endo- and phenotype-specific patterns of inflammatory mediators, receptor expression and single-cell secretomes.