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：
8469921
负责人：
Zinaida S Vexler
金额：
$ 35.07万
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：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8469921
关键词：
Adult Affect Animals Beds Behavior Bioluminescence Blood Vessels Brain Cells Child Diffusion Magnetic Resonance Imaging Docking Elements Endothelial Cells Endothelium Family Galectin 3 Generations Goals Growth Associated Protein 43 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 Outcome 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 clinically relevant cost cytokine density disability functional outcomes gain of function in vivo injured loss of function macrophage migration monocyte neuroblast neurogenesis postnatal promoter public health relevance 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（由申请人提供）：成人或新生儿中风后具有自我修复的潜力，但内源性神经发生是短暂且无效的。我们的目标是通过血管生成促进成人中风后的神经发生。大脑巨噬细胞可以通过影响大脑微环境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。 (Gal-3) 最近被认为与血管生成过程有关。Gal-3 为神经血管生态位的形成提供“对接点”并介导 VEGF 诱导的血管生成的能力使得该分子成为有吸引力的靶点。增强修复，但其对新生儿中风后修复的影响尚不清楚，我们使用我们建立的模型，部分通过增强 Gal-3 依赖性血管生成来研究小胶质细胞/巨噬细胞对新生儿中风后的长期恢复的影响。通过对新生大鼠和小鼠短暂性大脑中动脉闭塞的研究，我们将确定血管生成和神经发生是否依赖于脑巨噬细胞中产生的 Gal-3。在目标 1 中，我们将确定小胶质细胞耗竭对新生儿中风后血管生成和神经血管生态位形成的影响。我们将通过生物发光监测活体动物的轴突生长。在目标 2 中，我们将通过超声研究增强或破坏的 Gal-3 信号对活体大鼠内皮激活的影响。用特定的分子探针增强目标 ¿ vss3 整合素。将在 TLR2 启动子下携带双 luc/gfp 报告基因的新生缺血性 Gal-3 敲除小鼠中进一步研究修复。在目标 3 中，我们将通过以下方法描绘受损伤的活体大鼠中 Gal-3 或 VEGFR2 抑制后的神经血管生态位形成。使用超声和特定探针检测 VEGF 介导的血管生成，将确定受伤的 Gal-3 敲除小鼠的功能后果。新生儿中风后的 Gal-3 操作将被确定，了解调节修复的机制是成功从实验室转移到床上以增强受损新生儿大脑修复的重要第一步。