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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

基本信息

批准号：
10331887
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
项目类别：
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/10331887
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 antagonist 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

项目摘要

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.

摘要