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: 10203222
• 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/10203222
• 关键词: Acute; Affect; Age; Agonist; Annexin A1; Attenuated; Blood Circulation; Blood Vessels; Blood coagulation; Brain Injuries; Brain hemorrhage; CD36 gene; Cerebrospinal Fluid; Chronic; Clinical Management; Coagulation Process; Data; Development; FPR2 gene; Female; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Genes; Genetic Transcription; Glycoproteins; Goals; Hematoma; Hemorrhage; Hydrocephalus; Infant; Inflammation; Literature; Live Birth; MAP Kinase Gene; MAPK3 gene; Microglia; Morbidity - disease rate; Nervous System Physiology; Neuraxis; Neurologic Deficit; Neurological outcome; Newborn Infant; Outcome; Pathway interactions; Patients; Perinatal subependymal hemorrhage; Phagocytes; Phagocytosis; Phenotype; Play; Pregnancy; Premature Infant; Primary Cell Cultures; Protein phosphatase; Recovery; 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; absorption; base; clinical translation; clinically relevant; effective therapy; improved; improved outcome; infancy; knock-down; lipoxin A4; macrophage; male; monocyte; mortality; neonatal brain; 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、死亡和获得性婴儿病的主要原因之一 美国早产儿脑积水的临床治疗进展甚微。血 研究表明，GMH 后，血栓会破坏正常脑脊液，从而引发继发性脑损伤 生发基质出血引起出血后脑积水后的循环和吸收 发展。目前的实验证据表明，快速血肿消退对于快速消除血肿是必要的。 减轻炎症并改善出血性中风后的神经系统结果。 N-甲酰肽受体 2 (FPR2) 是一种 G 蛋白偶联受体，已被证明对中风后具有神经保护作用。 FPR2 激活有 与吞噬巨噬细胞清除率的上调有关，但其机制尚未明确 充分探索。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是一种跨膜糖蛋白，在小胶质细胞吞噬血液中起着至关重要的作用 GMH 后血块清除。 FPR2 已被证明可以激活细胞外信号调节激酶 1/2 (ERK1/2)， 它促进双特异性蛋白磷酸酶 1 (DUSP1) 基因的转录。当前文献 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 激活可增强血肿消退并改善神经功能缺损。 因此，我们试图阐明 FPR2 的潜在血肿消除机制。我们假设 FPR2 刺激通过激活 ERK 增强小胶质细胞诱导的血肿消退 (1/2)/DUSP1/CD36 信号通路，从而改善短期和长期神经系统结果。 目标 1 将研究 FPR2 在增强血肿消退中的作用，从而改善神经功能 遵循 GMH 的功能。目标 2 将研究 FPR2 诱导的 ERK/DUSP1/CD36 信号传导激活 GMH 之后的途径。该提案的长期目标是为FPR2的临床转化提供基础 刺激作为一种有效的非侵入性治疗策略，可预防急性和慢性并发症 在 GMH 患者群体中。