Role of neutrophil extracellular traps (NETs) in impaired Fracture in type 2 diabetics

糖尿病是世界上患病率和发病率最高的代谢性疾病。该病与许多并发症有关，尽管治疗复杂且费用密集，但往往对健康造成严重损害。不仅糖尿病患者，糖尿病前期患者的骨骼结构也发生了改变。因此，糖尿病前期患者比新陈代谢正常的人更容易骨折。因此，假定糖尿病前期患者和以前未确诊的糖尿病患者（估计德国未报告病例数）的比率约为。450万)在创伤手术中尤其高。在骨折的情况下，骨块的固定，周围软组织的处理以及患者随后的活动都是巨大的挑战。愈合过程往往较长，并发症较多，其中患肢截肢并不是个例。在德国，治疗这些并发症占糖尿病直接相关费用的很大一部分。为了提高对糖尿病前期患者骨折的治疗，我们的目标是在本项目中建立一种筛查方法，使糖尿病前期患者能够在早期阶段被发现，从而有针对性地进行治疗。通过优化血糖控制（药物），并发症的风险已经可以降低。然而，为了在未来开发靶向治疗，需要对潜在机制有一个基本的了解。骨折后，中性粒细胞是到达骨折血肿的第一批细胞。在小鼠模型中显示，糖尿病刺激中性粒细胞形成NETs（中性粒细胞胞外陷阱）。在NETosis过程中，中性粒细胞从含有瓜氨酸组蛋白和抗菌肽的细胞中释放它们的DNA，以结合病原体并使其无害。我们怀疑糖尿病患者过度形成的NETs会损害周围组织，从而延迟或阻止伤口和骨折愈合。酶PADI4（肽基精氨酸脱亚胺酶4）在这个过程中起着特殊的作用。我们预计糖尿病患者中性粒细胞中PADI4水平升高，使细胞对NETosis刺激敏感。骨折后，糖尿病患者的氧化应激和亚硝化应激增加。我们怀疑这是NETosis的关键触发因素。此外，我们的初步工作表明PADI4的遗传变异影响中性粒细胞对NETosis刺激的反应强度。这反过来又决定了糖尿病前期/糖尿病患者对并发症的易感性，如组织和植入物相关感染。本提案的目的是证明这些假设和假设，并确定可能的潜在机制。在这个项目中获得的知识将在未来用于开发新的治疗方法，以支持糖尿病前期/糖尿病患者的伤口和骨折愈合。

Diabetes mellitus is the metabolic disorder with the highest prevalence and incidence worldwide. The disease is associated with numerous complications, which, despite complex and cost-intensive treatment, often cause serious damage to health. Not only diabetics but already prediabetics show an altered bone structure. As a result, pre-/diabetics suffer more often from fractures than those with healthy metabolism. It is therefore assumed that the rate of prediabetics and previously unrecognized diabetics (estimated number of unreported cases in Germany approx. 4.5 million) is particularly high in trauma surgery. In the case of a fracture, the fixation of the bone pieces, the handling of the surrounding soft tissue and the following mobilization of the patient represent great challenges. The healing process is often prolonged and rich in complications, among which the amputation of the affected limbs is not an isolated case. Treating these complications accounts for a large proportion of the direct diabetes-associated costs in Germany.In order to improve the treatment of fractures in pre-/diabetics, we aim to establish a screening during this project that enables pre-/diabetics to be identified at an early stage so that they can be treated in a targeted manner. The risk of complications can already be reduced through optimized blood sugar control (medication). However, in order to develop targeted therapies in the future, a fundamental understanding of the underlying mechanisms is required. After a fracture, neutrophils are the first cells arriving in the fracture hematoma. In a mouse model it was shown that diabetes stimulates neutrophils to form NETs (neutrophil extracellular traps). In the process of NETosis, neutrophils release their DNA from the cell with citrullinated histones and antimicrobial peptides in order to bind pathogens and render them harmless. We suspect that an excessive formation of NETs in diabetics damages the surrounding tissue and thus delays or prevents wound and fracture healing. The enzyme PADI4 (peptidyl arginine deiminase 4) plays a special role in this process. We expect increased levels of PADI4 in neutrophils from diabetics, sensitizing the cells for NETosis stimuli. After a fracture, diabetics experience increased oxidative and nitrosative stress. We suspect that this is a critical trigger for the NETosis. In addition, our preliminary work suggests that the genetic variants of PADI4 influence how strongly the neutrophils respond to the NETosis stimuli. This in turn determines the susceptibility of pre-/diabetics to complications such as tissue and implant-associated infections. Aim of this proposal is to prove these assumptions and hypotheses and to identify possible underlying mechanisms. The knowledge gained within this project will be used in the future to develop new therapeutic approaches to support wound and fracture healing in pre-/diabetics.