Pericyte mechanisms in traumatic brain injury

创伤性脑损伤的周细胞机制

• 批准号: 9902555
• 负责人: Eng H. Lo
• 金额: $ 38.06万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902555
• 关键词: Acute; Address; Astrocytes; Blood Vessels; Brain Concussion; Brain Injuries; Bromodeoxyuridine; Carbon Monoxide; Cell Culture Techniques; Cell Death; Cerebrovascular Disorders; Coculture Techniques; Data; Dependence; Electron Microscopy; Etiology; Event; Expression Profiling; Extracellular Matrix; Extravasation; Gases; Gene Expression; Heme; Homeostasis; Human; Hypoxia; In Vitro; Injury; Integrins; Knock-out; Knockout Mice; Knowledge; Label; Link; Maps; Mechanics; Mediating; Medicine; Modeling; Molecular; Mus; Nature; Neurological outcome; Neurons; Nitric Oxide; Nitric Oxide Pathway; Oxygenases; Pathway interactions; Pericytes; Pharmacology; Publishing; Recovery; Role; Signal Transduction; Small Interfering RNA; Source; Stretching; TBI treatment; Testing; Therapeutic; Transgenic Mice; Traumatic Brain Injury; Traumatic Brain Injury recovery; base; brain endothelial cell; controlled cortical impact; experimental study; gray matter; heme oxygenase-1; improved; improved outcome; in vivo; inhibitor/antagonist; injured; loss of function; mouse model; mutant; nerve stem cell; neurogenesis; novel; novel therapeutics; oligodendrocyte precursor; optical imaging; precursor cell; response; spatiotemporal; vascular injury; white matter

Pericyte Mechanisms in Traumatic Brain injury Pericyte mechanisms are poorly understood in TBI. This is the major gap in knowledge that we seek to address. Our pilot data (some published in Choi et al, Nature Medicine 2016) suggest that (a) pericytes are widely damaged in mouse models of concussion or controlled cortical impact, (b) pericyte injury involves HIF- 1a signaling, (c) disruption of pericyte-neural stem cell (NSC) crosstalk perturbs neurogenesis and interferes with TBI recovery, (d) pericyte-NSC crosstalk may involve nitric oxide (NO) pathways, (e) pericytes may also communicate with oligodendrocyte precursor cells (OPCs), and (f) treatments with carbon monoxide (CO) that enhance heme oxygenase (HO-1) signaling may restore pericyte crosstalk and improve recovery after TBI. Based on these pilot data, we propose this overall hypothesis: TBI triggers HIF-1a-mediated injury to pericytes and disrupts pericyte-NSC-OPC crosstalk thus interfering with endogenous recovery. If true, this hypothesis may have translational significance, i.e. rescuing “help-me” signaling between pericytes, NSCs and OPCs may improve gray and white matter recovery after TBI. We will test this hypothesis in four integrated aims. In Aim 1, we investigate cellular mechanisms that allow pericytes to support NSCs and OPCs, and ask how HIF-1a-mediated pericyte injury disrupts these crosstalk mechanisms. In Aim 2, we test CO as a way to augment HO-1 signaling for protecting pericytes. In Aim 3, we dissect integrin and HIF mechanisms for pericytes, NSCs and OPCs in vivo using two TBI models (mild-to-moderate concussion and more severe controlled cortical impact). In Aim 4, will use the two mouse models of concussion and controlled cortical impact to test the utility of CO-HO-1 signaling as a therapeutic approach for restoring pericyte-NSC-OPC crosstalk and improving recovery after TBI. To assess causality in our pathways, we will conduct gain and loss- of-function experiments using cell culture, in vivo mouse models, pharmacologic inhibitors, dominant mutant constructs, siRNA and knockouts, optical imaging and long-term neurological outcomes. This project should define a novel mechanism wherein widespread injury to pericytes underlie not only acute vascular injury after TBI, but also disrupts pericyte-NSC-OPC crosstalk pathways. Our findings may provide a new conceptual framework for potentially targeting pericyte mechanisms after TBI.

创伤性脑损伤中的周细胞机制 在TBI中，周细胞机制对其进行了鲜为人知。这是我们寻求的知识的主要差距 地址。我们的飞行员数据（一些发表在Choi等人，自然医学2016年）表明（a）周细胞是 （b）周围损伤在咨询或受控皮质影响的小鼠模型中受到广泛损害，涉及HIF- 1a信号传导，（c）围绕周围神经干细胞（NSC）串扰的破坏神经发生和干扰 随着TBI恢复，（d）Pericyte-NSC串扰可能涉及一氧化氮（NO）途径，（e）周细胞也可能 与少突胶质细胞前体细胞（OPC）和（f）用一氧化碳（CO）进行沟通 增强血红素加氧酶（HO-1）信号传导可能会恢复周细胞串扰并改善TBI后的恢复。 基于这些试验数据，我们提出了这一总体假设：TBI触发HIF-1A介导的周细胞伤害 并破坏周细胞NSC-OPC串扰，从而干扰内源性恢复。如果是真的，这个假设 可能已经翻译了意义，即营救周细胞，NSC和OPC之间的“帮助我”信号 改善TBI后灰质和白质的恢复。我们将在四个综合目的中检验这一假设。 在AIM 1中，我们研究了允许周细胞支持NSC和OPC的细胞机制，并询问如何 HIF-1A介导的周细胞损伤破坏了这些串扰机制。在AIM 2中，我们测试CO作为一种方式 增强HO-1信号用于保护周细胞。在AIM 3中，我们剖析整联蛋白和HIF机制 使用两种TBI模型（轻度至中度咨询，更严重 受控皮质影响）。在AIM 4中，将使用两种鼠标咨询模型和受控的皮质模型 测试Co-HO-1信号作为恢复周细胞-NSC-OPC的治疗方法的影响 TBI后串扰和改善恢复。为了评估我们的途径因果关系，我们将进行收益和损失 - 使用细胞培养，体内小鼠模型，药物抑制剂，显性突变体的功能实验 结构，siRNA和敲除，光学成像和长期神经系统结果。 该项目应定义一种新的机制，在这种机制中，对周细胞的宽度不仅是急性 TBI后的血管损伤，但也破坏了周细胞NSC-OPC串扰途径。我们的发现可能会提供 TBI之后可能靶向周围机制的新概念框架。