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Neuroinflammation and vascular development in GMH

GMH 的神经炎症和血管发育

基本信息

批准号：
10685146
负责人：
Eric J Huang
金额：
$ 58.07万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685146
关键词：
Agonist Anti-Bacterial Agents Bioenergetics Bioinformatics Biological Assay Blood Vessels Brain Brain region Cell Communication Cell Maturation Cell Nucleus Cells Cellular Stress Cerebral Palsy Cerebral cortex Complex Data Defensins Development Disease Disease model Elastases Endothelial Cells Enzymes Erythro Exhibits Fluorescence-Activated Cell Sorting Histologic Human In Vitro Inflammatory Interneurons Knowledge Lead Macrophage Mediating Microglia Molecular Morphogenesis Myelogenous Neonatal Mortality Neurodevelopmental Disorder Neuroglia Neuroimmune Organoids PTPRC gene Pathogenesis Perinatal subependymal hemorrhage Peroxidases Population Pregnancy Premature Birth Premature Infant Prevalence Property Radial Research Research Project Grants Role Second Pregnancy Trimester Signal Transduction Testing angiogenesis antagonist cytotoxic improved insight matrigel migration monocyte neonatal death nerve stem cell nestin protein neural circuit neuroblast neurogenesis neuroinflammation neuropathology neutrophil prenatal progenitor single-cell RNA sequencing stem cell biology therapeutic target transcriptomic profiling transcriptomics

项目摘要

SUMMARY Preterm infants born between 21 to 30 gestational weeks (GW) have 20-40% chance of developing germinal matrix hemorrhage (GMH), which is a leading cause of neonatal mortality and neurodevelopmental disorders, such as cerebral palsy. Despite decades of research, however, there has been no significant improvement in the prevalence of preterm birth and the mechanism leading to GMH remains unclear. To understand the cause(s) for GMH, we have shown that, during the second trimester, germinal matrix contains enriched populations of Nestin+ radial glia and DCX+ neuroblasts that are fated to become GABAergic interneurons. Furthermore, DCX+ neuroblasts in the germinal matrix are organized as distinct clusters, called DCX-Enriched Nests or DENs, where they expand and migrate to the cerebral cortex and other deep nuclei before becoming mature GABAergic interneurons and integrating into the local neural circuits. To investigate why blood vessels in the germinal matrix are particularly vulnerable to develop GMH, we combined histological and ultrastructural analyses, fluorescence- activated cell sorting (FACS), and single-cell transcriptomics to characterize the properties of nascent blood vessels in the prenatal human brain from 15 to 25 GW. These studies lead to three main conclusions. First, during the second trimester the vascular network in the germinal matrix is much more complex than other brain regions. These nascent blood vessels are tiled by an ensemble of endothelial cells and mural cells, which follow distinct developmental trajectories and use diverse signaling mechanisms to facilitate cell-cell communication and maturation. Second, endothelial cells from younger brain (15-18 GW) exhibit stage-specific transcriptomic and bioenergetic features that are different from those from 20-23 GW. In addition, microglia-vasculature interactions stage-dependently promote angiogenesis in the germinal matrix, but not in the cortical plate. Finally, transcriptomic profiling of CD45+ cells in GMH cases showed that proinflammatory neutrophils and monocytes utilize antibacterial factors and CXCL16-S1PR1 signaling, respectively, to disrupt nascent vasculature in the germinal matrix. Collectively, our results support the overarching hypothesis that proinflammatory neutrophils and monocytes produce cytotoxic factors to disrupt angiogenesis and neurogenesis in the germinal matrix of preterm infants with GMH. To test this hypothesis, we propose to (1) characterize the cytotoxic properties of neutrophil-produced antibacterial factors in disrupting angiogenesis, (2) determine the impacts of CXCL16-S1PR1-mediated signaling in angiogenesis in the germinal matrix, and (3) examine the impacts of GMH on the neurogenesis and migration of GABAergic interneurons. Results from this project will provide important insights into disease mechanism of, and therapeutic targets for, GMH.

总结