Serum markers of brain barriers

描述（由申请人提供）：血脑屏障（BBB）保护大脑免受系统性影响，并积极参与中枢神经系统稳态的控制。血脑屏障功能丧失在各种神经系统疾病中很常见。根据所涉及的神经系统状况，并考虑到血脑屏障也会阻止有用的化疗药物进入，血脑屏障的开放可能是有利的，也可能是有害的。血脑屏障衰竭的确切时间过程及其对疾病进展的病因学贡献尚不清楚，主要是因为可靠的外周标志物不可用，而且血脑屏障的黄金放射学标准尚未确定。发现血脑屏障功能的成像策略或替代标记物被确定为本项目公告的重中之重。我们的初步结果表明，特定脑或脑脊液蛋白（例如S100P）的外周测量是可重复的，侵入性较小且成本较低的替代对比CT/MRI或脑脊液取样来确定血脑屏障完整性。一种替代的、容易获得的、非放射学的血脑屏障功能受损的标志物，可能在识别各种神经系统疾病患者中具有重要价值，包括转移性脑肿瘤、胶质瘤、中风、多发性硬化症、头部损伤等。我们开发了一种多步骤的常规方法，可以检测血脑屏障打开前后的血浆蛋白。许多问题仍未得到解答。S100P是血脑屏障功能唯一有用的外周标志物吗？标志物积累的时间进程是怎样的？假定的标记物如何与不同的MRI/CT模式相关联，被认为与血脑屏障渗漏相关？我们将使用分子和蛋白质检测技术来发现血脑屏障完整或渗漏的新标志物，并验证血浆与脑脊液中S100P或其他血脑屏障标志物的比值增加与血脑屏障损伤的放射测量在时间和质量上相关的假设。最后，我们将验证这些标记物在早期检测复发性脑肿瘤或转移中的有用性，以具体解决该PA的任务之一。

DESCRIPTION (provided by applicant): The blood-brain barrier (BBB) shields the brain from systemic influences, and actively participates to the control of central nervous system homeostasis. Loss of BBB function is common in a variety of neurological disorders. Depending on the neurological condition involved and given the fact that the BBB also prevents entry of useful chemotherapeutic agents, BBB openings may be both advantageous and damaging. The exact time course of BBB failure, and its etiological contribution to disease progression is poorly understood mainly because reliable peripheral markers are not available and since golden radiologic standards of BBB are yet to be determined. The discovery of imaging strategies or surrogate markers of BBB function were identified a top priority for this Program announcement. Our preliminary results suggest that peripheral measurements of specific brain or CSF proteins (e.g. S100P) are reproducible, less invasive and less costly alternative to contrast CT/MRI or CSF sampling for determining BBB integrity. A surrogate, readily available, non-radiologic marker for impaired BBB function may be of significant value in identifying patients with a variety of neurological disorders, including metastatic brain tumors, gliomas, stroke, multiple sclerosis, head injury, etc. We developed a multi-step routine that allows detection of plasma proteins prior to and after BBB opening. Many questions remain unanswered. Is S100P the only useful peripheral marker of BBB function? What is the time course of the marker's accumulation? How do putative markers correlated with different MRI/CT patterns believed to be associated with BBB leakage? We will use molecular and protein-detection techniques to discover new markers of BBB intactness or leakage and to test the hypothesis that an increased plasma-to CSF ratio of S100P or other BBB markers correlates temporally and qualitatively with radiological measures of BBB impairment. Finally, we will validate the usefulness of these markers in the early detection of recurrent brain tumors or metastases, to specifically address one of the mandates of this PA.