Harnessing blood clot clearance mechanisms after germinal matrix hemorrhage

利用生发基质出血后的血凝块清除机制

• 批准号: 10528489
• 负责人: Jiping Tang
• 金额: $ 39.5万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10528489
• 关键词: Acute; Affect; Age; Agonist; Annexin A1; Attenuated; Blood Vessels; Blood coagulation; Brain Injuries; Brain hemorrhage; CD36 gene; Central Nervous System; Cerebrospinal Fluid; Chronic; Circulation; Clinical Management; Coagulation Process; Data; Development; FPR1 gene; FPR2 gene; Female; Functional disorder; G-Protein-Coupled Receptors; Genes; Genetic Transcription; Goals; Hematoma; Hemorrhage; Hydrocephalus; Infant; Inflammation; Literature; Live Birth; MAP Kinase Gene; MAPK3 gene; Macrophage; Membrane Glycoproteins; Microglia; Morbidity - disease rate; Nervous System Physiology; Neurologic Deficit; Neurological outcome; Newborn Infant; Outcome; Pathway interactions; Patients; Perinatal subependymal hemorrhage; Phagocytes; Phagocytosis; Phagocytosis Induction; Phenotype; Play; Pregnancy; Premature Infant; Primary Cell Cultures; Protein phosphatase; Recovery; Reducing Agents; Regimen; Research; Resolution; Rodent; Rodent Model; Role; Rupture; Signal Pathway; Signaling Protein; Specificity; Stroke; Subependymal; Testing; Therapeutic; Therapeutic Agents; Treatment Protocols; United States; Up-Regulation; Ventricular; absorption; antagonist; clinical translation; clinically relevant; effective therapy; improved; improved outcome; infancy; knock-down; lipoxin A4; male; monocyte; mortality; neonatal brain; neuroprotection; p38 Mitogen Activated Protein Kinase; patient population; post stroke; pre-clinical; protective effect; receptor; recruit; scavenger receptor

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.

抽象的 生发基质出血（GMH）是发病率，死亡率和获得的婴儿的主要原因之一 美国早产儿的脑积水，其临床管理几乎没有进展。血 通过破坏正常的脑脊液，凝块已显示在GMH后引起继发性脑损伤 生发基质出血后的循环和吸收，导致止血后脑积水 发展。当前的实验证据表明，快速的血肿分辨率是快速的 减轻炎症并改善出血性中风后神经系统效果。 N-甲基肽受体 2（FPR2）是一种G蛋白偶联受体，已显示在中风后是神经保护性。 FPR2激活具有 与吞噬巨噬细胞清除的上调有关，但其机制尚未 完全探索。最近的文献表明，FPR2可能在刺激清道夫受体中发挥作用 CD36。清道夫受体CD36，一种跨膜糖蛋白，在小胶质细胞中起着至关重要的作用 GMH后的凝块清除率。已显示FPR2激活细胞外信号调节激酶1/2（ERK1/2）， 促进双特异性蛋白磷酸酶1（DUSP1）基因的转录。目前的文献 表明DUSP1可能作用于CD36受体，并可能在FPR2诱导的吞噬作用中发挥作用。我们的 初步表明，FPR2激活增强了血肿的分辨率并改善了神经系统缺陷。 因此，我们试图阐明FPR2的潜在血肿分辨机理。我们假设这一点 FPR2刺激通过激活ERK增强了小胶质细胞诱导的血肿分辨率 （1/2）/dusp1/cd36信号通路，从而改善了短期和长期神经系统结局。 AIM 1将研究FPR2在增强血肿的分辨率中的作用，从而改善神经系统 GMH之后的功能。 AIM 2将研究FPR2诱导的ERK/DUSP1/CD36信号的激活 GMH之后的途径。该提案的长期目标是为FPR2的临床翻译提供基础 刺激是一种有效的非侵入性治疗策略，可防止急性和慢性并发症 在GMH患者人群中。