Mechanisms of VEGF Action in Intact and Grafted CNS

完整和移植中枢神经系统中 VEGF 的作用机制

• 批准号: 6751581
• 负责人: JEFFREY M ROSENSTEIN
• 金额: $ 28.88万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6751581
• 关键词: angiogenesis; blood brain barrier; brain disorder chemotherapy; brain disorders; brain injury; corpus striatum; dopamine; drug delivery systems; electron microscopy; gamma aminobutyrate; growth factor receptors; immunocytochemistry; immunoglobulin G; in situ hybridization; injection /infusion; laboratory rat; membrane permeability; nervous system transplantation; neuropharmacology; neuropil; neurotrophic factors; neutralizing antibody; stereotaxic techniques; technology /technique development; vascular endothelial growth factors

DESCRIPTION (provided by applicant): The purpose of this proposal is .to understand the mechanisms of VEGF action after its administration to the CNS with respect to permeability and angiogenesis and to utilize VEGF's effects to create methods to circumvent the blood-brain barrier (BBB) with minimal invasiveness. Although VEGF and its receptors are known to be upregulated after injury, little information exists on its application to brain tissue. Experiments will attempt to explore models of VEGF as a permeability agent restricted to specific brain areas that will serve as a portal to subsequently allow intravascular administration of compounds that would never cross the BBB rapid access to neuropil. Previous attempts to disrupt the BBB have been global nature and produced random and disseminated openings; in contrast this proposal examines BBB disruption in a strictly focal manner. Aims 1 and 2 examine VEGF angiogenic and permeability effects either after direct focal application by acute or chronic convection enhanced microinfusion (Aim 1) or indirectly using our novel method of grafting isolated clusters of VEGF-treated brain microvessels (Aim 2) to restricted areas of striatum. The spatial and temporal degree of permeability and its receptor-mediation will be examined, and in both Aims we will determine in principle, the feasibility of intravascular delivery of certain non-permeable bioactive compounds such as radiolabeled dopamine (DA), GABA, or the neurotrophic factor, GDNF. Because consistent and effective BBB circumvention is presently perceived as exceptionally difficult problem in neurobiology, the long range goals are to elucidate whether VEGF with its unique permeability, angiogenic and anti-apoptotic properties could be an important agent for molecular delivery in CNS interventional paradigms. These studies may provide impetus for the further design strategies for the circumvention of the BBB and/or the targeting of VEGF receptor mediated effects in brain injury.

描述（由申请人提供）：该提案的目的是了解VEGF作用在渗透性和血管生成方面给CNS施用后的机制，并利用VEGF的效果来创建方法以最小的侵入性来规避血脑屏障（BBB）的方法。尽管已知VEGF及其受体在受伤后被上调，但几乎没有有关其应用于脑组织的信息。实验将尝试探索VEGF的模型作为限制在特定大脑区域的渗透性剂，这些渗透性剂将作为门户，以便随后允许血管内给药化合物，这些化合物永远不会越过BBB快速进入Neuropil。以前打扰BBB的尝试是全球性质，并产生了随机和传播的开口。相比之下，该提案以严格的焦点方式检查了BBB的破坏。目标1和2检查通过急性或慢性对流直接应用局灶性施用后的VEGF血管生成和渗透性效应增强了微灌注（AIM 1），或间接使用我们的新方法，用于将VEGF治疗的VEGF处理的脑脑脑脑脑脑的隔离簇（AIM 2）（aim 2）用于纹状体的限制区域。将检查空间和时间的渗透性及其受体中等程度，在这两个方面，我们都将确定某些不可渗透性的生物活性化合物（如放射性生物活性化合物，例如放射性化多巴胺（DA），GABA），GABA或Neuretrophicapolophicapolicaphic rophicapic因子，gdnf的可行性。由于目前将一致且有效的BBB规避视为神经生物学中异常困难的问题，因此远程目标是阐明VEGF具有其独特的渗透性，血管生成和抗凋亡特性是否可能是CNS介入范式中分子递送的重要药物。这些研究可能为绕过BBB的进一步设计策略提供动力，并靶向VEGF受体介导的脑损伤作用。