Pericyte mechanisms in traumatic brain injury

创伤性脑损伤的周细胞机制 TBI中的周细胞机制知之甚少。这是我们寻求的知识的主要差距， 地址.我们的试验数据（一些发表在Choi等人，Nature Medicine 2016）表明，（a）周细胞是 在脑震荡或受控皮质撞击的小鼠模型中广泛受损，（B）周细胞损伤涉及HIF-1 α。 1a信号传导，（c）周细胞-神经干细胞（NSC）串扰的破坏扰乱神经发生并干扰 随着TBI恢复，（d）周细胞-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）通讯，和（f）用一氧化碳（CO）处理， 增强血红素加氧酶（HO-1）信号传导可以恢复周细胞串扰并改善TBI后的恢复。 基于这些初步数据，我们提出了这一总体假设：TBI触发HIF-1a介导的周细胞损伤 并破坏周细胞-NSC-OPC串扰，从而干扰内源性恢复。如果这是真的， 可能具有翻译意义，即拯救周细胞、NSC和OPCs之间的“帮助我”信号可能 改善TBI后灰质和白色物质恢复。我们将在四个综合目标中检验这一假设。 在目标1中，我们研究了允许周细胞支持NSC和OPCs的细胞机制， HIF-1a介导的周细胞损伤破坏了这些串扰机制。在目标2中，我们测试CO作为一种方法， 增强HO-1信号通路以保护周细胞。在目标3中，我们剖析了整合素和HIF的机制， 使用两种TBI模型（轻度至中度脑震荡和更严重的脑震荡）， 控制皮质冲击）。在目标4中，将使用两种脑震荡小鼠模型和受控皮质 测试CO-HO-1信号传导作为恢复周细胞-NSC-OPC的治疗方法的效用的影响 串扰和改善TBI后的恢复。为了评估因果关系，我们将进行得与失- 使用细胞培养、体内小鼠模型、药理学抑制剂、显性突变体的功能丧失实验 构建体、siRNA和敲除、光学成像和长期神经学结果。 该项目应确定一种新的机制，其中周细胞的广泛损伤不仅是急性 TBI后的血管损伤，但也破坏周细胞-NSC-OPC串扰途径。我们的发现可能会提供一个 TBI后潜在靶向周细胞机制的新概念框架。

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.