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（由申请人提供）：脑血流量与局部神经元需求相关。然而，如果没有软脑膜小动脉的上游扩张以允许更多的血液到达扩张的下游血管，这种耦合就会受到损害。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，软脑膜小动脉通过神经胶质界限（GL）与实质神经元隔离。中心假设是，所涉及的信号传导机制会随着神经元激活强度的增加而变化。为此，我们将在各种药理和分子干预下比较癫痫发作（局部荷包牡丹碱）和坐骨神经刺激（SNS）期间软脑膜小动脉的反应。将测试以下具体假设：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）。这些研究将使用经过验证的模型来选择性损伤 GL 或内皮细胞。 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 ATP 流出相关的信号传播。药理学阻断和 siRNA 相关敲低都将用于靶向特定 ATP 受体和 connexin-43。 3) GL 产生的旁分泌因子作用于软脑膜血管，引起松弛。主要候选者是 ATP 水解的 K+ 和分解产物（腺苷；ADP），通过核酸外切酶 (EN) 作用形成。将测试特定药理学阻断剂或 siRNA 相关的 K+ 释放通道（BKCa 和 Kir-4.1）和 EN 敲低对癫痫发作与 SNS 诱导的 PAD 的影响。 4) 释放的 K+ 和腺苷分别刺激软脑膜小动脉平滑肌上的 Kir-2.1 通道和腺苷 A2A 受体，可能是相互作用的。如上所述，将应用特定的药理学和基于 siRNA 的干预措施。这些结果将为了解神经元在活动增强期间如何向特定脑血管发出信号以扩张提供重要的新见解。由此产生的向激活神经元的营养输送增加可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舒张信号如何到达软脑膜小动脉仍不清楚。该项目的核心目标是确定神经元活动增加向软脑膜小动脉发出信号扩张的机制。中心假设是星形胶质细胞和神经胶质细胞代表神经激活引起的软脑膜小动脉扩张的重要信号传导通道。