Promotion of neurovascular remodeling through mitochondria transfer after stroke

中风后通过线粒体转移促进神经血管重塑

基本信息

批准号：
9009202
负责人：
Kazuhide Hayakawa
金额：
$ 37.8万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9009202
关键词：
Astrocytes Biological Markers Blood Vessels Brain Brain Injuries Calcium Cells Central Nervous System Diseases Cicatrix Coculture Techniques Confocal Microscopy Culture Media Cyclic ADP-Ribose Data Electron Microscopy Endothelial Cells Endothelium Etiology Glucose HMGB1 gene Heat shock proteins Human Image In Vitro Inflammation Ischemia Knowledge Label Magnetic Resonance Imaging Measures Mediating Membrane Potentials Microscope Mitochondria Mitogen-Activated Protein Kinases Molecular Morphology Mus Neurologic Neuronal Plasticity Neurons Oxygen Oxygen Consumption PECAM1 gene Pathway interactions Patients Pattern Permeability Production Rattus Recombinants Recovery Recovery of Function Recycling Signal Pathway Signal Transduction Small Interfering RNA Stem cells Stroke System Testing Time Vascular remodeling Western Blotting angiogenesis brain remodeling cell injury central nervous system injury deprivation extracellular immunocytochemistry improved in vivo kinase inhibitor mitochondrial membrane neural growth neurovascular unit neutralizing antibody new therapeutic target novel optical imaging particle post stroke progenitor public health relevance relating to nervous system repaired spatiotemporal stroke recovery synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Reactive astrocytes were traditionally thought to induce both detrimental and beneficial effects for brain remodeling after stroke. Here, we propose a new concept whereby reactive astrocytes can surprisingly transfer mitochondria into adjacent neurons and endothelial cells to promote neurovascular remodeling in damaged brain. Our overall hypothesis is as follows. Damage associated molecular pattern (DAMP) signals upregulate CD38 in reactive astrocytes. In addition, accumulating endothelial progenitor cells (EPCs) secrete soluble CD31 that further amplify CD38 signaling. Altogether, this gliovascular crosstalk induces astrocytes to release of extracellular particles containing mitochondria. Mitochondria are then transferred into neurons and endothelium, thus enhancing neuroplasticity, BBB repair, angiogenesis and overall neurovascular recovery. Our pilot data are intriguing: (i) DAMPs or soluble CD31 upregulate CD38 in astrocytes, (ii) CD38 signaling causes astrocytes to release extracellular mitochondria, (iii) confocal microscopy reveals transfer of astrocytic mitochondria into neurons and endothelial cells, (iv) extracellular mitochondria enhance neural growth and angiogenesis, (v) suppression of astrocytic CD38 with siRNA inhibits neuronal plasticity after focal ischemia, and (vi) extracellular particles with functional mitochondria can e detected in CSF from human stroke patients. We will test 3 specific aims in this project. In Aim 1, we will investigate mechanisms of extracellular mitochondria particle production in reactive astrocytes. In Aim 2, we will dissect mechanisms of astrocytic mitochondria transfer for enhancing neurovascular remodeling. Finally in Aim 3, we will demonstrate that remodeling vascular signals promote mitochondria transfer from reactive astrocytes into neurons and endothelial cells after stroke in vivo. This study should define a novel mechanism of glial-EPCs crosstalk to enhance neurovascular remodeling and provide a new concept for mitochondrial transfer in the neurovascular unit.

描述（由申请人提供）：传统上认为反应性星形胶质细胞既能引起疼痛，又能对中风后的大脑重塑产生有益作用。在这里，我们提出了一个新概念，即反应性星形胶质细胞可以令人惊讶地将线粒体转移到邻近的神经元和内皮细胞中，以促进中风后的神经血管重塑。我们的总体假设如下：损伤相关分子模式 (DAMP) 信号上调反应性星形胶质细胞中的 CD38。分泌可溶性 CD31，进一步放大 CD38 信号传导。总之，这种胶质血管串扰诱导星形胶质细胞释放含有线粒体的细胞外颗粒，然后转移到神经元和内皮细胞中，从而增强神经可塑性、血脑屏障修复、血管生成和整体神经血管恢复。有趣的是：(i) DAMP 或可溶性 CD31 上调星形胶质细胞中的 CD38，(ii) CD38 信号传导导致星形胶质细胞释放细胞外线粒体，(iii) 共聚焦显微镜揭示星形细胞线粒体转移至神经元和内皮细胞，(iv) 细胞外线粒体增强神经生长和血管生成，(v) 用 siRNA 抑制星形细胞 CD38 可抑制局灶性缺血后的神经元可塑性，(vi)可以在人类中风患者的脑脊液中检测到具有功能性线粒体的细胞外颗粒。我们将在该项目中测试 3 个具体目标。在目标 1 中，我们将研究细胞外的机制。在目标 2 中，我们将剖析星形胶质细胞线粒体转移增强神经血管重塑的机制。最后，在目标 3 中，我们将证明重塑血管信号促进中风后线粒体从反应性星形胶质细胞转移到神经元和内皮细胞。这项研究应该定义一种新的神经胶质-EPCs串扰机制，以增强神经血管重塑，并为神经血管单元中的线粒体转移提供新概念。