Regulatory mechanisms of temporal microglia phenotype expression in a neonatal rat model of infection-sensitized hypoxic ischemic brain injury

感染致敏缺氧缺血性脑损伤新生大鼠模型颞部小胶质细胞表型表达的调控机制

• 批准号: 422493683
• 负责人: Professor Dr. Hemmen Sabir
• 金额: --
• 依托单位: Klinik für Kinderheilkunde I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/422493683?language=en
• 关键词: Regulatory; mechanisms; temporal; microglia; phenotype

Perinatal asphyxia, describing the lack of oxygen and blood flow before, during, or just after birth, is one of the leading causes of global child death. It can affect all organ systems, however the most frightened resulting condition, predominantly affecting the newborn brain, is hypoxic ischemic encephalopathy (HIE) often resulting in mortality or significant morbidity in later life. Even though therapeutic hypothermia (TH) has become standard treatment for HIE, around 50% of cooled newborns still die or develop severe disability. Early identification of these non-responders is not possible yet, but urgently needed, as they might benefit from additional treatment options. Perinatal infection increases the vulnerability to hypoxic-ischemic injuries and negatively influences the prognosis of affected newborns. We have developed an animal model of infection-sensitized hypoxic-ischemic brain injury (double-hit model) and showed that TH is not a viable treatment option in this model, characterizing one group of non-responders. This double-hit model gives us the opportunity to investigate the underlying mechanisms in a defined group of non-responders. We have shown that microglia cells are key players in our double-hit model and contribute to brain injury. As the interaction and regulation of the double-hit is not known yet, this project aims to describe the regulatory mechanisms responsible for microglia activation and different microglia phenotype expression in our double-hit model of inflammation-sensitized hypoxic-ischemic brain injury in newborn rats. We will focus on the role of micro-RNAs in microglia modulation and phenotype expression over time. Additionally, we will investigate the role of the NLRP3 inflammasome, its impact during microglia activation, its regulation by miRNAs and its impact on severity of brain injury in our double-hit model. Last, we will investigate the potency of an additional neuroprotective treatment (Erythropoietin) in our double-hit model, describing its influence and pathway on microglia phenotype activation. The aim is to develop robust biomarkers and therapeutic targets, which will be tested in clinical studies, early identifying non-responders to therapeutic hypothermia.

围产期窒息是指出生前、出生期间或出生后不久缺乏氧气和血流，是全球儿童死亡的主要原因之一。它可以影响所有器官系统，但最令人恐惧的疾病是缺氧缺血性脑病 (HIE)，主要影响新生儿大脑，通常导致死亡或晚年显着发病。尽管治疗性低温 (TH) 已成为 HIE 的标准治疗方法，但约 50% 的低温新生儿仍然死亡或出现严重残疾。早期识别这些无反应者尚不可能，但迫切需要，因为他们可能受益于额外的治疗选择。围产期感染增加了缺氧缺血性损伤的脆弱性，并对受影响的新生儿的预后产生负面影响。我们开发了一种感染敏感性缺氧缺血性脑损伤（双重打击模型）的动物模型，并表明 TH 不是该模型中可行的治疗选择，其特征是一组无反应者。这种双重打击模型使我们有机会研究一组定义的无反应者的潜在机制。我们已经证明，小胶质细胞是我们的双重打击模型中的关键角色，并导致脑损伤。由于双重打击的相互作用和调节尚不清楚，本项目旨在描述新生大鼠炎症敏感缺氧缺血性脑损伤双重打击模型中负责小胶质细胞激活和不同小胶质细胞表型表达的调节机制。我们将重点关注 micro-RNA 随着时间的推移在小胶质细胞调节和表型表达中的作用。此外，我们将研究 NLRP3 炎症小体的作用、其在小胶质细胞激活过程中的影响、miRNA 的调节及其对双击模型中脑损伤严重程度的影响。最后，我们将研究双重打击模型中额外的神经保护治疗（促红细胞生成素）的效力，描述其对小胶质细胞表型激活的影响和途径。目的是开发强大的生物标志物和治疗靶点，将在临床研究中进行测试，及早识别对低温治疗无反应的人。