Harnessing blood clot clearance mechanisms after germinal matrix hemorrhage

摘要 生发基质出血(GMH)是婴儿发病率、死亡率和获得性婴儿的主要原因之一。 美国早产儿脑积水的临床治疗进展甚微。血样 已有研究表明，血栓会破坏正常的脑脊液，从而导致GMH后继发性脑损伤。 生发基质出血致出血性脑积水后的循环和吸收 发展。目前的实验证据表明，血肿迅速消退是必要的 改善出血性中风后的炎症反应和神经预后。N-甲酰基多肽受体 2(FPR2)是一种G蛋白偶联受体，已被证明在中风后具有神经保护作用。FPR2激活有 与巨噬细胞吞噬清除功能上调有关，但其机制尚不清楚。 充分探索。最近的文献表明，FPR2可能在清道夫受体的刺激中起作用 CD36。清道夫受体CD36是一种跨膜糖蛋白，在小胶质细胞吞噬血中起重要作用 GMH后血块清除。FPR2可以激活细胞外信号调节蛋白1/2(ERK1/2)， 促进双特异性蛋白磷酸酶1(DUSP1)基因的转录。当代文学 提示DUSP1可能作用于CD36受体，并可能在FPR2诱导的吞噬功能中发挥作用。我们的 初步研究表明，激活FPR2可提高血肿消退，改善神经功能缺失。 因此，我们试图阐明FPR2的血肿溶解机制。我们假设 FPR2刺激通过激活ERK促进小胶质细胞诱导的血肿溶解 (1/2)/DUSP1/CD36信号通路，从而改善短期和长期神经预后。 目标1将研究FPR2在促进血肿消退方面的作用，从而改善神经功能 GMH之后的功能。AIM 2将研究FPR2诱导的ERK/DUSP1/CD36信号的激活 GMH后的通路。这项建议的长期目标是为FPR2的临床翻译提供基础 刺激作为预防急性和慢性并发症的有效非侵入性治疗策略 在GMH患者群体中。

Abstract Germinal matrix hemorrhage (GMH) is one of the leading causes of morbidity, mortality, and acquired infantile hydrocephalus in preterm infants in the United States, with little progress made in its clinical management. Blood clots have been shown to elicit secondary brain injury after GMH, by disrupting normal cerebrospinal fluid circulation and absorption after germinal matrix hemorrhage causing post-hemorrhagic hydrocephalus development. Current experimental evidence suggests that rapid hematoma resolution is necessary to quickly ameliorate inflammation and improve neurological outcomes after hemorrhagic stroke. N-formyl peptide receptor 2 (FPR2), a G-protein-coupled receptor, has been shown to be neuroprotective after stroke. FPR2 activation has been associated with the upregulation of phagocytic macrophage clearance, yet its mechanism has not been fully explored. Recent literature suggests that FPR2 may play a role in the stimulation of scavenger receptor CD36. Scavenger receptor CD36, a trans-membrane glycoprotein, plays a vital role in microglia phagocytic blood clot clearance after GMH. FPR2 has been shown to activate extracellular-signal-regulated kinase 1/2 (ERK1/2), which promotes the transcription of the dual-specificity protein phosphatase 1 (DUSP1) gene. Current literature suggests that DUSP1 may act on CD36 receptor and may play a role in FPR2 induced phagocytosis. Our preliminary suggests that FPR2 activation enhances hematoma resolution and improves neurological deficits. Therefore, we seek to elucidate the underlying hematoma resolving mechanism of FPR2. We hypothesize that FPR2 stimulation enhances microglia induced hematoma resolution through the activation of the ERK (1/2)/DUSP1/CD36 signaling pathway, thereby improving short- and long-term neurological outcomes. Aim 1 will investigate the role of FPR2 in enhancing hematoma resolution, thereby improving neurological function following GMH. Aim 2 will investigate FPR2-induced activation of the ERK/DUSP1/CD36 signaling pathway after GMH. The long-term goal of this proposal is to provide a basis for clinical translation of FPR2 stimulation as an effective non-invasive therapeutic strategy to protect against acute and chronic complications in the GMH patient population.