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）：脑血流量与局部神经元需求相关。然而，如果软膜小动脉没有上游扩张以允许更多的血液到达扩张的下游血管，这种耦合将受到损害。起源于神经元的血管舒张信号到达软脑膜小动脉的过程尚不清楚，软脑膜小动脉是由胶质界膜（GL）从实质神经元中分离出来的。核心假设是，所涉及的信号机制将随着神经元激活强度的增加而变化。为此，我们将比较在癫痫发作（局部荷包牡丹碱）和坐骨神经刺激（SNS）的各种药理学和分子干预的存在下，软膜小动脉的反应。将检验以下特定假设：1）神经元活化通过涉及星形胶质细胞（和GL）和血管内皮的信号传导过程诱导软脑膜小动脉扩张（PAD）。这些研究将使用经验证的GL或内皮选择性损伤模型。2)神经元激活诱导的PAD涉及星形胶质细胞网络和间隙连接和/或半通道内的ATP流出相关信号传播。药理学阻断和siRNA连接的敲低都将用于靶向特异性ATP受体和连接蛋白-43。3)由GL产生的旁分泌因子作用于软脑膜血管以引起松弛。主要的候选者是K+和ATP水解的分解产物（腺苷; ADP），通过外核苷酸酶（EN）作用形成。将检测特异性药物阻断剂或K+释放通道（BKCa和Kir-4.1）和EN的siRNA相关敲低对癫痫发作vs SNS诱导的PAD的影响。4)释放的K+和腺苷，分别刺激Kir-2.1通道和腺苷A2 A受体，可能相互作用，软脑膜小动脉平滑肌。如上所述，将应用特定的药理学和基于siRNA的干预。这些结果将为神经元在活动增强期间如何向特定的脑血管发出扩张信号提供重要的新见解。由此产生的向激活的神经元输送营养的增加起到确保正常脑功能的作用，并在病理状态下提供保护。起源于神经元的血管扩张信号如何到达软膜小动脉仍不清楚。这个项目的核心目标是确定机制，通过增加神经元活动信号软膜小动脉扩张。中心假设是，星形胶质细胞和胶质细胞界膜代表了一个重要的信号传导管道软脑膜小动脉扩张所产生的神经激活。