Serum markers of brain barriers

描述(申请人提供)：血脑屏障(BBB)保护大脑免受全身影响，并积极参与控制中枢神经系统的动态平衡。血脑屏障功能丧失在各种神经系统疾病中很常见。根据所涉及的神经状况，并考虑到血脑屏障也阻止有用的化疗药物进入的事实，血脑屏障开口可能是有利的，也可能是有害的。BBB衰竭的确切时间进程及其对疾病进展的病因作用尚不清楚，主要是因为可靠的外周标志物不可用，以及BBB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该计划公告的首要任务。我们的初步结果表明，对特定的脑或脑脊液蛋白(如S100P)进行外周测量是确定血脑屏障完整性的CT/MRI或脑脊液对比采样的替代方法，具有重复性好、侵入性小、成本低的特点。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记物可能对识别各种神经疾病的患者具有重要价值，包括转移性脑瘤、胶质瘤、中风、多发性硬化症、脑损伤等。我们开发了一种多步骤程序，允许在血脑屏障开放前后检测血浆蛋白。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？标记物积累的时间进程是什么？被认为与血脑屏障渗漏相关的不同MRI/CT模式与推定的标记物有何关联？我们将使用分子和蛋白质检测技术来发现BBB完整性或渗漏的新标记物，并检验S100P或其他BBB标记物的血浆/脑脊液比率增加与BBB损害的放射测量在时间和质量上存在相关性的假设。最后，我们将验证这些标记物在早期发现复发脑瘤或转移中的有用性，以具体处理该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.