BIOCHEMICAL CONTROL OF BBB IN ABNORMAL BRAIN CAPILLARIES

描述（改编自申请人的摘要）： R01应用程序将进一步评价生化变化沿着 脑毛细血管的改变将导致血脑 屏障（BBB）和血肿瘤屏障（BTB）的通透性。这些障碍可能是 选择性地开放了一段时间，如果这种机制 调节可以识别，它可能是有可能的药物靶向特定的 受伤或有肿瘤的脑区。校长以往的成绩 研究者建议有可能选择性地打开BBB或BTB 通过调节缓激肽2（B2）受体、一氧化氮（NO）、环 GMP（cGMP）和钙依赖性钾（KCa）通道。缓激肽 这些屏障的介导开放经由这些屏障的顺序调节而发生。 机制等然而，这种调制的精确蜂窝位置是不确定的。 未知目前的建议将评估个别细胞类型的作用 介导不同内皮细胞中不同渗透性反应 人口。这些将使用脑肿瘤的大鼠模型在体内进行评估 和伤害。具体目的：（1）评价缓激肽的结合位点 并评估各种尺寸分子的传递系数（Ki）值， 与B2受体密度和功能的关系，（2）评估NO的作用， 可溶性鸟苷酸环化酶（sGC）、cGMP依赖性蛋白激酶和KCa通道 以及（3）确定不同大小的分子或病毒 颗粒通过紧密连接或反式连接穿过正常或受损的BBB 血管活性物质的输注可能 引发这种渗透性变化。拟议工作的结果 在增强和潜在的靶向药物输送到大脑的影响。

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.