The role of ribonuclease A superfamily as a therapeutic target in septic cardiomyopathy.

核糖核酸酶 A 超家族作为脓毒症心肌病治疗靶点的作用。

• 批准号: 522498104
• 负责人: Privatdozent Dr. Lukas Martin
• 金额: --
• 依托单位: Klinik für Operative Intensivmedizin und Intermediate Care
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/522498104?language=en
• 关键词: role; ribonuclease; superfamily; therapeutic; target

Sepsis is one of the leading causes of death in german intensive care units. According to the definition, it is a systemic inflammatory reaction resulting from an infection. Depending on the severity, it affects the organs. Septic cardiomyopathy is a feared complication of sepsis and will be studied as an example of multi-organ failure in this project. The systemic inflammatory response is induced, among others, by Damage Associated Molecular Patterns (DAMPs) that are released during sepsis. DAMPs are endogenous intracellular molecules that are released from injured or dying cells and cause an inflammatory response. Extracellular RNA (eRNA) belongs to the group of DAMPS and has been shown to have harmful effects on the heart. These deleterious effects of eRNA can be limited by its degradation by naturally occurring ribonuclease (RNases). RNases are components of the innate immune system, belong to the group of endogenous antimicrobial peptides and modulate the local and systemic inflammatory response induced by Pathogen Associated Molecular Patterns (PAMPs) and DAMPs. Human RNase inhibitor 1 (RNH1) is ubiquitously expressed in a variety of tissues and inhibits RNases. In our own preliminary studies we could show that in septic patients RNase 1, 3 and 7 as well as RNH1 are elevated compared to healthy volunteers. In addition, in a murine model of polymicrobial sepsis, we demonstrated that application of RNase 1 reduces cardiac dysfunction and apoptosis in vivo. However, the course of RNases 1, 3, and 7 serum levels and their associations with the clinical course of patients with sepsis and the influence of various DAMPs and PAMPs on their secretion remain unclear. Also unresolved is the role of RNH1 in cardiac dysfunction in vitro and in vivo. The aim of this translational project is to further investigate the role of the RNase A family and its inhibitor RNH1 in septic cardiomyopathy. Serum levels of the proteins will be evaluated in patients with sepsis and the underlying secretion mechanisms will be further analyzed in vitro. The influence of the RNase A family and RNH1 will be further investigated in vivo in a murine polymicrobial sepsis model with respect to their impact on cardiac dysfunction. In the last program point, mechanisms of RNases apart from their nucleolytic function as well as their anti-inflammatory activity in cardiomyocytes will be investigated. In addition, the extent to which RNH1 itself plays an anti-inflammatory role in the PAMPs/DAMPs-induced inflammatory response in cardiomyocytes will be investigated.

败血症是德国重症监护病房死亡的主要原因之一。根据定义，它是由感染引起的全身炎症反应。根据严重程度，它会影响器官。脓毒性心肌病是脓毒症的一种可怕的并发症，本项目将作为多器官功能衰竭的一个例子进行研究。全身炎症反应是由脓毒症期间释放的损伤相关分子模式（DAMPs）引起的。DAMPs是内源性的细胞内分子，从受伤或死亡的细胞中释放出来，引起炎症反应。细胞外RNA （eRNA）属于DAMPS组，已被证明对心脏有有害影响。eRNA的这些有害作用可以通过自然发生的核糖核酸酶（rnase）的降解来限制。rnase是先天免疫系统的组成部分，属于内源性抗菌肽，可调节由病原体相关分子模式（Pathogen Associated Molecular Patterns, PAMPs）和DAMPs诱导的局部和全身炎症反应。人RNase inhibitor 1 （RNH1）在多种组织中普遍表达并抑制RNase。在我们自己的初步研究中，我们可以表明，与健康志愿者相比，脓毒症患者的RNase 1、3和7以及RNH1升高。此外，在小鼠多微生物脓毒症模型中，我们证明了RNase 1在体内的应用可以减少心功能障碍和细胞凋亡。然而，RNases 1、3和7的血清水平及其与脓毒症患者临床病程的关系以及各种DAMPs和PAMPs对其分泌的影响尚不清楚。RNH1在体外和体内心功能障碍中的作用也未得到解决。本转化项目的目的是进一步研究RNase A家族及其抑制剂RNH1在脓毒性心肌病中的作用。脓毒症患者的血清蛋白水平将被评估，潜在的分泌机制将在体外进一步分析。RNase A家族和RNH1的影响将在小鼠多微生物脓毒症模型中进一步研究其对心功能障碍的影响。在最后一个程序点，RNases除其核溶解功能和抗炎活性外，在心肌细胞中的机制将被研究。此外，RNH1本身在PAMPs/ damps诱导的心肌细胞炎症反应中发挥抗炎作用的程度也将被研究。