BIOCHEMICAL CONTROL OF BBB IN ABNORMAL BRAIN CAPILLARIES

描述(改编自申请人的摘要)：本竞争续期 R01应用程序将进一步评估生化变化 大脑毛细血管的改变会导致血脑的改变 屏障(BBB)和血-肿瘤屏障(BTB)通透性。这些障碍可能是 有选择地在短时间内开放，如果这样的机制 可以识别调制方式，有可能针对特定的药物 受伤或有肿瘤的脑区。校长以前的研究结果 研究人员建议，有可能有选择地打开血脑屏障或血脑屏障 通过调节缓激肽2(B2)受体，一氧化氮(NO)，环状 GMP(CGMP)和钙依赖钾(Kca)通道。缓激肽 这些屏障的介导性打开是通过顺序地调制这些 机械装置。然而，这种调制的准确蜂窝位置是 未知。目前的提案将评估单个细胞类型的作用 介导不同内皮细胞的不同通透性反应 人口。这些方法将在体内用大鼠脑肿瘤模型进行评估。 和受伤。具体目标是：(1)评价缓激肽的结合部位 并计算了不同大小分子的传递系数 与B2受体密度和功能的关系，(2)评估NO的作用， 可溶性鸟苷环化酶(SGC)、cGMP依赖的蛋白激酶和KCA通道 通透性，以及(3)确定不同大小的分子或病毒 粒子通过紧密连接或运输穿过正常或受损的血脑屏障 内皮小泡途径和血管活性物质的输注可能 启动这种渗透性变化。拟议工作的结果是 对增强的和潜在的靶向药物向大脑输送的影响。

DESCRIPTION (adapted from applicant's abstract): This Competing Renewal of an R01 application will further evaluate how biochemical changes along with modification of brain capillaries will lead to alterations in blood-brain barrier (BBB) and blood-tumor barrier (BTB) permeability. These barriers can be selectively opened for brief periods of time and if the mechanism of such modulation can be identified, it may be possible to target drugs to specific injured or tumor bearing brain regions. Previous results by the principal investigator suggest that it may be possible to selectively open the BBB or BTB through modulation of bradykinin 2 (B2) receptors, nitric oxide (NO), cyclic GMP (cGMP) and calcium-dependent potassium (KCa) channels. The bradykinin mediated opening of these barriers occurs via a sequential modulation of these mechanisms. However, the precise cellular location of such modulation is unknown. The current proposal will evaluate the role of individual cell types that mediate differential permeability responses in different endothelial cell populations. These will be evaluated in vivo using rat models of brain tumors and injury. The Specific Aims will: (1) evaluate binding sites for bradykinin and evaluate transfer coefficient (Ki) values for various sized molecules in relation to B2 receptor density and function, (2) assess the role of NO, soluble guanylate cyclase (sGC), cGMP-dependent protein kinase and KCa channels in permeability, and (3) determine if molecules of differing size or viral particles cross normal or compromised BBB by tight junctions or trans endothelial vesicle routes and if infusion of vasoactive substances may initiate such permeability changes. The results of the proposed work have implications in enhanced and potentially targeted drug delivery to the brain.