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Collaborative Research Center 1149

Danger Response, Disturbance Factors and Regenerative Potential after Acute Trauma

Trauma as a mechanical injury to tissue affects a vast number of people worldwide at any time throughout their life. The trauma-triggered acute danger response induces potent regeneration and healing processes. However, significant complications, including systemic inflammation and organ dysfunction, may develop post trauma, particularly in the presence of numerous disturbance factors (e.g. co-morbidities). The underlying pathophysiological mechanisms are complex and currently poorly understood. Furthermore, clinical trauma management on all levels requires early recognition and pathophysiological understanding of the trauma reaction and deduction of effective individualised therapeutic strategies.

Focusing on the most common injury patterns, major disturbance factors, and regenerative mechanisms, the proposed Collaborative Research Centre (CRC) 1149 at Ulm University aims to provide profound pathomechanistic understanding of the systemic and local cellular and molecular trauma responses and related complications for transfer into effective therapeutic trauma strategies.

Several unique features of the centre will facilitate realisation of the integrative and translational approach; these include a cross-disciplinary and highly collaborative scientific environment within the zmfu (Centre of Musculoskeletal Research Ulm), the Clinical Research Unit KFO200 and the Trans-regional Research Unit 793, and the long-standing commitment of the Medical Faculty at Ulm University to cutting-edge basic, (re)translational, and clinical research in trauma. These attributes are complemented by sophisticated, clinically relevant in vitro and in vivo models of the trauma impact and resulting complications to gain deep insights into the mechanistic complexity and regeneration potential post trauma as well as to evaluate innovative cell- and molecular based therapies.

As compelling scientific and clinical challenges, central hypotheses are defined in the CRC, proposing to:

A) better understand the danger response after trauma on a molecular, cellular, organ, and organism level;

B) determine the influence of major disturbance factors (co-morbidities) on the trauma response;

C) define mechanisms of the dysfunction and potential of regeneration post trauma and adapt them to trauma management.

These central hypotheses are reflected by three project groups (A, B, and C) that will closely interact with each other, combining excellent basic research with clinical expertise:

Research group A will investigate the acute pro- and anti-inflammatory danger response after trauma including early cellular and molecular danger sensing, -translation, -clearance and -escalation mechanisms. This group of projects focuses on danger-associated molecular patterns (DAMPs) and their consequences on early organ-blood barrier failure, synaptic (re)modelling, key inflammatory pathways (including NF-κB), and changes of the first line of cellular defence. 

In close collaboration, research group B will address the modulation and perturbation of the posttraumatic response by the most relevant co-morbidities (e.g. atherosclerosis, chronic obstructive pulmonary disease, and obesity) and substance abuse (e.g. nicotine and alcohol), and, furthermore, will identify long-term effects of multiple personal factors (e.g. age) in regard to healing processes in humans.

Furthering perceptions of project groups A and B, research group C pursues “resolving mechanisms” of the posttraumatic inflammatory response and the regenerative capacity, focusing on the role of pro- and antiinflammatory mediators (e.g. IL-6, corticosteroids) in tissue regeneration, and defining mobilisation/homing  mechanisms and the therapeutic potential of stem cells to improve healing processes after severe trauma.

For future-oriented avenues, early pro-regenerative responses will be investigated to generate new hypotheses and novel strategic thinking to fully restore tissue defects. In the long-term perspective, a valid functional immune monitoring of the individual danger response on the background of various co-morbidities and adapted immune- and cell-based therapies, for example by complement intervention and large-scale GMPgrade cellular ex vivo expansion, are anticipated.

Finally, the proposed CRC provides a superb opportunity to closer define and realise the concept of (re)translational research “from bedside to bench and back” for the danger response after tissue trauma. This approach will substantially contribute to a better understanding of trauma pathophysiology under “reallife” conditions, and, importantly, to an improved clinical management and outcome for trauma patients.

CRC 1149 image film

CRC 1149 Image Film

Research and Training at the Medical Faculty, Ulm University

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