Harnessing blood clot clearance mechanisms after germinal matrix hemorrhage

摘要 老年性基质出血（GMH）是导致发病率、死亡率和获得性婴儿出血的主要原因之一。 在美国，早产儿脑积水的临床治疗进展甚微。血液 凝块已被证明可通过破坏正常脑脊液而引起GMH后的继发性脑损伤 再生基质出血后的循环和吸收导致出血后脑积水 发展目前的实验证据表明，快速血肿消退是必要的， 改善出血性卒中后的炎症和神经功能结局。n-甲酰基肽受体 2（FPR 2），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。FPR 2激活具有 与吞噬巨噬细胞清除的上调有关，但其机制尚未被证实。 充分探索。最近的文献表明，FPR 2可能在刺激清道夫受体中起作用 CD36。清道夫受体CD 36是一种跨膜糖蛋白，在小胶质细胞吞噬血液中起重要作用 GMH后血凝块清除。FPR 2已显示激活细胞外信号调节激酶1/2（ERK 1/2）， 其促进双特异性蛋白磷酸酶1（DUSP 1）基因的转录。当前文献 提示DUSP 1可能作用于CD 36受体，并可能在FPR 2诱导的吞噬作用中发挥作用。我们 初步表明FPR 2激活增强血肿消退并改善神经功能缺损。 因此，我们试图阐明FPR 2的潜在血肿溶解机制。我们假设 FPR 2刺激通过激活ERK增强小胶质细胞诱导的血肿消退 （1/2）/DUSP 1/CD 36信号通路，从而改善短期和长期神经功能结局。 目的1将研究FPR 2在增强血肿消退中的作用，从而改善神经功能 功能遵循GMH。目标2将研究FPR 2诱导的ERK/DUSP 1/CD 36信号传导激活 GMH之后的路径。该提案的长期目标是为FPR 2的临床翻译提供基础。 刺激作为一种有效的非侵入性治疗策略，以防止急性和慢性并发症 在GMH患者人群中。

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.