Coordination Funds

全身炎症可能是对非感染性刺激的反应，也可能是在感染病原体时发生。很明显，深入了解刺激和患者特定的分子病理生理途径，确定特定的患者内型，才能将特定的治疗方法应用于分层的患者队列。同样，必须承认，并不是所有的患者都表现出相同的临床表型。患者之间的个体差异和全身炎症的多模式原因当然解释了为什么这些先前的因果治疗方法到目前为止还没有被证明对未分层的患者集体有效。深入了解控制某些治疗方案成败的分子机制将是成功识别特定患者群体以及开发和建立个性化治疗方法的关键。第一个资助期的中心目标是确定和调查在全身炎症和败血症期间器官损伤所涉及的相关分子、免疫和细胞途径，从而确定和调查治疗策略。在许多情况下，我们成功地完成了这项任务，例如，揭示了新的外源性和内源性分子机制，提供了对全身炎症引起的急性肾损伤的保护，确定了控制肺内免疫反应的分子途径，并证明了在全身炎症后的后期阶段，单核细胞和巨噬细胞中存在明显的分子开关，决定了炎症的生理分解或免疫低反应的持久性。在CRU342的第二个资助期，我们坚持我们最初的概念，专注于连接基础科学和临床研究的总体目标，将翻译研究带到一个新的水平。我们将为未来使用个体化治疗方法治疗全身炎症和器官功能障碍的试验提供可靠的基础。这只能通过将研究努力集中在疾病/症状特定内型和特定表型的调查上来实现。这涉及到根据患者特定的内源性和表型确定患者队列，这些患者使用一种针对在这一亚群中占主导地位的信号通路的药物进行特定治疗。我们的方法还包括对临床先导研究中确定的治疗目标进行临床验证和确认，以及将从第一个资助期的临床研究中获得的假设生成观察结果反向转换为基础科学项目的新探索性研究目标。这包括确定炎症介质、受体表达和单细胞分泌体的内源性和表型特异性模式。

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.