Coordination Funds

协调基金

• 批准号: 427828061
• 负责人: Professor Dr. Alexander Zarbock
• 金额: --
• 依托单位: Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/427828061?language=en
• 关键词: Coordination; Funds

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.

全身性炎症可响应于非感染性刺激或在感染病原体后发展。很明显，需要深入了解刺激和患者特异性分子病理生理学途径，定义特定的患者内型，以将特定的治疗方法应用于分层患者队列。同样，必须承认，并非所有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性炎症的多模式原因肯定代表了为什么这些先前的因果治疗方法迄今为止尚未被证明对未分层的患者群体有效的解释。更深入地了解决定某些治疗方案成功或失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识别和研究全身性炎症和脓毒症期间器官损伤所涉及的相关分子、免疫和细胞途径，从而识别和研究治疗性治疗策略。在许多情况下，我们已经成功地完成了这一使命，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，确定了控制肺部免疫反应的分子途径，并证明了单核细胞和巨噬细胞中存在不同的分子开关，这些开关决定了炎症的生理消退或免疫功能低下的持续性。在全身性炎症后的后期阶段的反应性。在CRU 342的第二个资助期内，我们坚持我们最初的概念，专注于基础科学和临床研究的总体目标，将转化研究提升到一个新的水平。我们将为未来使用个体化治疗方法治疗全身性炎症和器官功能障碍的试验提供可靠的基础。这只能通过将研究工作集中在疾病/综合征特异性内型和特异性表型的调查上来实现。这涉及基于其特异性内分泌和表型来鉴定患者队列，所述患者队列用靶向在该亚群中占主导地位的信号传导途径的药剂进行特异性治疗。我们的方法还包括临床验证和确认临床试点研究中确定的治疗目标，以及在第一个资助期内从临床研究中获得的假设生成观察结果的反向翻译，作为基础科学项目的新探索性研究目标。这涉及到炎症介质、受体表达和单细胞分泌物的内源性和表型特异性模式的鉴定。