Astrocytes and neurovascular coupling

星形胶质细胞和神经血管耦合

• 批准号: 7385481
• 负责人: DALE Alan PELLIGRINO
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-05 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385481
• 关键词: ATP Hydrolysis; ATP Receptors; Ablation; Address; Adenosine; Adenosine A2A Receptor; Anatomy; Astrocytes; Attention; Bicuculline; Blood; Blood Vessels; Brain; Cells; Cephalic; Cerebrovascular Circulation; Cerebrum; Communication; Connexin 43; Coupled; Coupling; Elements; Endothelium; Ensure; Gap Junctions; Injury; Intervention; Label; Link; Metabolic; Metabolism; Microcirculation; Microscopy; Modeling; Molecular; Monitor; Neuroglia; Neurons; Numbers; Nutrient; Pathologic; Pathway interactions; Potassium Channel; Process; Rattus; Receptor Activation; Relaxation; Risk; Role; Seizures; Signal Transduction; Smooth Muscle; Techniques; Testing; Thick; Transducers; Vascular Endothelium; Vascular Smooth Muscle; arteriole; barium chloride; base; computerized data processing; digital; ecto-nucleotidase; extracellular; improved; in vivo; insight; paracrine; receptor; relating to nervous system; research study; response; sciatic nerve

DESCRIPTION (provided by applicant): Cerebral blood flow is coupled to local neuronal demands. However, this coupling would be compromised without upstream dilation in pial arterioles to permit more blood to reach dilated downstream vessels. The process that permits vasodilating signals, originating in neurons, to reach the pial arterioles, which are isolated from parenchymal neurons by the glia limitans (GL), is unclear. The central hypothesis is that the signaling mechanisms involved will vary as the intensity of the neuronal activation increases. To that end, we will compare pial arteriolar responses during seizure (topical bicuculline) and sciatic nerve stimulation (SNS) in the presence of a variety of pharmacologic and molecular interventions. The following specific hypotheses will be tested: 1) Neuronal activation induces pial arteriolar dilation (PAD) via a signaling process involving astrocytes (and the GL) and vascular endothelium. These studies will use validated models for selective injury to the GL or endothelium. 2) Neuronal activation-induced PAD involves ATP efflux-related signal propagation within astrocytic networks and gap junctions and/or hemichannels. Both pharmacologic blockade and siRNA-linked knockdown will be used to target specific ATP receptors and connexin-43. 3) Paracrine factors arising from the GL act on pial vessels to elicit relaxation. The leading candidates are K+ AND breakdown products of ATP hydrolysis (adenosine; ADP), formed via ectonucleotidase (EN) action. The effects of specific pharmacologic blockers or siRNA-linked knockdown of K+ release channels (BKCa and Kir-4.1) and ENs, on seizure- vs SNS-induced PAD will be tested. 4) The released K+ and adenosine, respectively, stimulate Kir-2.1 channels and adenosine A2A receptors, perhaps interactively, on pial arteriolar smooth muscle. As above, specific pharmacologic and siRNA-based interventions will be applied. The results will provide vital new insights into how neurons, during periods of enhanced activity, signal specific cerebral vessels to dilate. The resulting increase in nutrient delivery to activated neurons acts to ensure normal brain function and provides protection in pathologic states. How vasodilating signals, originating in the neurons, reach the pial arterioles remain unclear. The core objective of this project is to identify mechanisms through which increased neuronal activity signals pial arterioles to dilate. The central hypothesis is that astrocytes and the glia limitans represent a vital signaling conduit in the pial arteriolar dilation arising from neural activation.

描述（由申请人提供）：脑血流与局部神经元需求耦合。但是，这种耦合将被妥协，而无需在海岸小动脉上游扩张，以允许更多的血液到达扩张的下游血管。尚不清楚允许源自神经元的血管散发信号到达丘疹动脉的过程，该小动脉从实质神经元中分离为胶质神经元（GL）尚不清楚。中心假设是，随着神经元激活的强度增加，所涉及的信号传导机制将有所不同。为此，我们将在存在多种药理学和分子干预的情况下比较癫痫发作（局部双核）和坐骨神经刺激（SNS）期间的毛小动脉反应（SNS）。将测试以下特定假设：1）神经元激活通过涉及星形胶质细胞（以及GL）和血管内皮细胞的信号传导过程诱导脊椎小动脉扩张（PAD）。这些研究将使用经过验证的模型对GL或内皮进行选择性损伤。 2）神经元激活诱导的垫涉及星形细胞网络和间隙连接和/或半通道内ATP外排相关的信号传播。药理学阻滞和与siRNA相关的敲低将用于靶向特定的ATP受体和连接蛋白43。 3）旁分泌因子是由对pial血管的GL ACT引起的，以引起松弛。主要的候选者是通过纤维法酶（EN）作用形成的ATP水解（腺苷； ADP）的K+和分解产物。特定的药理阻滞剂或K+释放通道（BKCA和KIR-4.1）和ENS的SIRNA连接敲低的影响，将测试癫痫发作与SNS诱导的PAD。 4）释放的K+和腺苷分别刺激KIR-2.1通道和腺苷A2A受体，也许是在伴有小动脉平滑肌上进行交互式的。如上所述，将采用特定的药理和基于siRNA的干预措施。结果将提供至关重要的新见解，即在活动增强期间神经元如何向特定的大脑血管进行扩张。由此导致的营养递送到激活的神经元的行为是为了确保正常的大脑功能并提供病理状态的保护。源自神经元的血管吞噬信号如何到达丘疹动脉尚不清楚。该项目的核心目的是确定神经元活性提高的机制，信号是pial动脉扩张。中心假设是，星形胶质细胞和胶质限极者代表了由神经激活引起的猫动脉扩张中的重要信号传导导管。