Macrophages as modulators of repair after neonatal stroke

巨噬细胞作为新生儿中风后修复的调节剂

基本信息

批准号：
8862546
负责人：
Zinaida S Vexler
金额：
$ 34.4万
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：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8862546
关键词：
Adult Affect Animals Beds Bioluminescence Blood Vessels Brain Cells Child Diffusion Magnetic Resonance Imaging Docking Elements Endothelial Cells Endothelium Family Galectin 3 Generations Goals Growth Associated Protein 43 Health Infant Inflammation Inflammatory Injection of therapeutic agent Injury Integrins Ischemic Penumbra Ischemic Stroke Knock-out Knockout Mice Life Live Birth Luciferases Mediating Microbubbles Microglia Middle Cerebral Artery Occlusion Modeling Molecular Probes Monitor Mus Neonatal Nerve Degeneration Neurons Newborn Infant Process Rattus Recovery Recovery of Function Reporter Rodent Role Signal Transduction Societies Stroke System TLR2 gene Translations Ultrasonography Up-Regulation Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors angiogenesis axonal sprouting behavioral outcome clinically relevant contrast enhanced cost cytokine density disability functional outcomes gain of function in vivo injured loss of function macrophage migration monocyte neuroblast neurogenesis postnatal promoter pup repaired response stroke recovery tool

项目摘要

DESCRIPTION (provided by applicant): There is a potential for self-repair after adult or neonatal stroke, but endogenous neurogenesis is short- lived and ineffective. Our goal is to enhance the repair after neonatal stroke. Angiogenesis facilitates neurogenesis after adult stroke through the formation of a "neurovascular niche." Brain macrophages can modulate repair and functional recovery after stroke through effects on the brain microenvironment and direct effects on angiogenesis and neurogenesis. Galectin-3 (Gal-3) has recently been implicated in the process of angiogenesis. The postulated ability of Gal-3 to provide a "docking point" for the formation of a neurovascular niche and to mediate VEGF-induced angiogenesis makes this molecule an attractive target for enhancing repair, but its effect on repair after neonatal stroke is not known. We hypothesize that microglia/macrophages critically affect long-term recovery after neonatal stroke, in part through enhanced Gal-3-dependent angiogenesis. Using our established models of transient middle cerebral artery occlusion in neonatal rats and mice, we wil determine whether angiogenesis and neurogenesis depend on Gal-3 produced in brain macrophages. In Aim 1, we will determine the effects of microglial depletion on angiogenesis and neurovascular niche formation after neonatal stroke. We will monitor axonal outgrowth in living animals by bioluminescence. In Aim 2, we will investigate the effects of enhanced or disrupted Gal-3 signaling on endothelial activation in living rats by ultrasound enhanced with specific molecular probes to target �vss3 integrin. Repair will be further studied in neonatal ischemic Gal-3 knockout mice bearing the dual luc/gfp reporter under the TLR2 promoter. In Aim 3, we will delineate neurovascular niche formation folowing Gal-3 or VEGFR2 inhibition in injured living rats by using ultrasound and specific probes for VEGFR2. VEGF-mediated angiogenesis will be determined in injured Gal-3 knockout mice. Functional consequences of microglial depletion and Gal-3 manipulations after neonatal stroke will be determined. Understanding the mechanisms regulating repair is an important first step on the way to successful bench-to-bed translation to enhance repair in injured newborn brains.

描述（由适用提供）：成人或新生儿中风后有自我修复的潜力，但内源性神经发生短暂而无效。我们的目标是增强新生儿中风后的维修。血管生成通过形成“神经血管生态位”后成年中风后促进神经发生。脑巨噬细胞可以通过对脑微环境的影响以及对血管生成和神经发生的直接影响来调节中风后的修复和功能恢复。 Galectin-3（Gal-3）最近在血管生成过程中暗示了。 Gal-3的假定能力为形成神经血管生态位的形成并介导VEGF诱导的血管生成的“对接点”的能力使该分子成为增强修复的有吸引力的目标，但尚不清楚其在新生儿中风后修复后的影响。我们假设小胶质细胞/巨噬细胞严重影响新生儿中风后的长期恢复，部分通过增强的GAL-3依赖性血管生成。使用我们既定的新生大鼠和小鼠中瞬时脑动脉闭塞的模型，我们将确定血管生成和神经发生是否取决于在脑巨噬细胞中产生的gal-3。在AIM 1中，我们将确定小胶质细胞部署对新生儿中风后的血管生成和神经血管生态裂形成的影响。我们将通过生物发光监测活动物中的轴突产物。在AIM 2中，我们将研究增强或破坏的GAL-3信号传导对活大鼠内皮激活的影响，通过增强活性大鼠的内皮激活，并具有特定的分子问题，以靶向``靶标VSS3整合素''。修复将进一步研究，在TLR2启动子下，带有双Luc/GFP报告基因的新生儿缺血性GAL-3基因敲除小鼠。在AIM 3中，我们将通过使用超声波和特定问题的VEGFR2来描述受伤的活大鼠中抑制Gal-3或VEGFR2抑制的神经血管生态位。 VEGF介导的血管生成将在受伤的GAL-3基因敲除小鼠中确定。新生儿中风后的小胶质部署和GAL-3操纵的功能后果将确定。了解该机制调节修复是成功进行基准翻译的途径的重要第一步，以增强受伤的新生大脑的维修。