Astrocytes and neurovascular coupling

星形胶质细胞和神经血管耦合

• 批准号: 7635776
• 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/7635776
• 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; 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(申请人提供)：脑血流与局部神经元需求相关联。然而，如果软脑膜小动脉没有上游扩张，使更多的血液进入扩张的下游血管，这种偶联就会受到影响。允许起源于神经元的血管扩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限制蛋白(GL)从实质神经元中分离出来的。中心假设是，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，我们将比较癫痫发作(外用荷包牡丹碱)和坐骨神经刺激(SNS)在各种药物和分子干预下的软膜小动脉反应。将检验以下特定假设：1)神经元激活通过涉及星形胶质细胞(和GL)和血管内皮细胞的信号过程来诱导软膜小动脉扩张(PAD)。这些研究将使用经过验证的选择性损伤GL或内皮的模型。2)神经元激活诱导的PAD涉及与ATP外流有关的信号在星形细胞网络、缝隙连接和/或半槽内的传递。药物阻断和siRNA连接的敲除都将被用于靶向特定的ATP受体和连接蛋白-43。3)GL产生的旁分泌因子作用于软脑膜血管，引起松弛。领先的候选者是K+和ATP水解的分解产物(腺苷；ADP)，通过电子核酸酶(EN)作用形成。将测试特定的药物阻滞剂或siRNA连接的K+释放通道(BKCa和KIR-4.1)和ENS的阻断对癫痫-VS SNS诱导的PAD的影响。4)释放的K+和腺苷分别兴奋软膜小动脉平滑肌上的KIR-2.1通道和腺苷A2a受体，可能是交互作用的。如上所述，将应用特定的药理学和基于siRNA的干预措施。这些结果将为神经元在活动增强期间如何发出扩张特定脑血管的信号提供至关重要的新见解。由此增加了对激活神经元的营养供应，以确保正常的大脑功能，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脑膜小动脉仍不清楚。这个项目的核心目标是确定神经元活动增加的机制，通过这些机制，软膜小动脉扩张。中心假说是星形胶质细胞和胶质细胞极限蛋白在神经激活引起的软脑膜小动脉扩张中是一个重要的信号通道。