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

• 批准号: 8677985
• 负责人: Zinaida S Vexler
• 金额: $ 33.97万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/8677985
• 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

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）：成人或新生儿卒中后有自我修复的潜力，但内源性神经发生是短暂且无效的。我们的目标是加强新生儿卒中后的修复。血管生成通过形成“神经血管龛”促进成人卒中后的神经发生。“脑巨噬细胞可以通过影响脑微环境和直接影响血管生成和神经发生来调节中风后的修复和功能恢复。半乳糖凝集素-3（Galectin-3，Gal-3）最近被认为参与血管生成过程。假定Gal-3能够为神经血管龛的形成提供“对接点”并介导VEGF诱导的血管生成，这使得该分子成为增强修复的有吸引力的靶标，但其对新生儿中风后修复的作用尚不清楚。我们推测，小胶质细胞/巨噬细胞严重影响新生儿中风后的长期恢复，部分是通过增强半乳糖苷-3依赖性血管生成。利用我们建立的新生大鼠和小鼠短暂性大脑中动脉闭塞模型，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卒中后血管生成和神经血管龛形成的影响。我们将通过生物发光来监测活体动物的轴突生长。在目标2中，我们将研究增强或破坏Gal-3信号传导对活体大鼠内皮激活的影响，通过用特异性分子探针超声增强靶向vss 3整合素。修复将在TLR 2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。在目标3中，我们将通过使用超声和VEGFR 2的特异性探针来描绘损伤的活体大鼠中Gal-3或VEGFR 2抑制后的神经血管生态位形成。VEGF介导的血管生成将在受损的Gal-3敲除小鼠中确定。将确定新生儿卒中后小胶质细胞耗竭和Gal-3操作的功能后果。了解调节修复的机制是成功进行从实验室到实验室的平移以增强受损新生儿大脑修复的重要第一步。