Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark.
Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark.
Fluids Barriers CNS. 2022 Jun 4;19(1):44. doi: 10.1186/s12987-022-00335-x.
Dysregulation of brain fluid homeostasis associates with brain pathologies in which fluid accumulation leads to elevated intracranial pressure. Surgical intervention remains standard care, since specific and efficient pharmacological treatment options are limited for pathologies with disturbed brain fluid homeostasis. Such lack of therapeutic targets originates, in part, from the incomplete map of the molecular mechanisms underlying cerebrospinal fluid (CSF) secretion by the choroid plexus.
The transcriptomic profile of rat choroid plexus was generated by RNA Sequencing (RNAseq) of whole tissue and epithelial cells captured by fluorescence-activated cell sorting (FACS), and compared to proximal tubules. The bioinformatic analysis comprised mapping to reference genome followed by filtering for type, location, and association with alias and protein function. The transporters and associated regulatory modules were arranged in discovery tables according to their transcriptional abundance and tied together in association network analysis.
The transcriptomic profile of choroid plexus displays high similarity between sex and species (human, rat, and mouse) and lesser similarity to another high-capacity fluid-transporting epithelium, the proximal tubules. The discovery tables provide lists of transport mechanisms that could participate in CSF secretion and suggest regulatory candidates.
With quantification of the transport protein transcript abundance in choroid plexus and their potentially linked regulatory modules, we envision a molecular tool to devise rational hypotheses regarding future delineation of choroidal transport proteins involved in CSF secretion and their regulation. Our vision is to obtain future pharmaceutical targets towards modulation of CSF production in pathologies involving disturbed brain water dynamics.
脑液动态平衡失调与脑病理学有关，其中液体积聚会导致颅内压升高。由于针对脑液动态平衡失调的病理学，特异性和有效的药物治疗选择有限，因此手术干预仍然是标准治疗方法。这种缺乏治疗靶点的情况部分源于对脉络丛脑脊液（CSF）分泌的分子机制的不完全了解。
通过荧光激活细胞分选（FACS）捕获的全组织和上皮细胞的 RNA 测序（RNAseq）生成大鼠脉络丛的转录组图谱，并与近端小管进行比较。生物信息学分析包括参考基因组映射，然后根据类型、位置以及与别名和蛋白质功能的关联进行过滤。根据转录丰度将转运体和相关调节模块排列在发现表中，并在关联网络分析中联系在一起。
脉络丛的转录组图谱在性别和物种（人、大鼠和小鼠）之间显示出高度相似性，而与另一种高容量液转运上皮组织——近端小管的相似性较低。发现表提供了可能参与 CSF 分泌的转运机制列表，并提出了调节候选物。
通过对脉络丛转运蛋白的转录丰度进行定量及其潜在的相关调节模块，我们设想了一种分子工具，可以对涉及 CSF 分泌及其调节的脉络丛转运蛋白进行合理化假设。我们的愿景是获得未来的药物靶点，以调节涉及脑水动力学紊乱的病理中的 CSF 产生。
