Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption.
Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption.
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DOI：
10.7150/thno.65064
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发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Price RJ
中科院分区：
文献类型：
--
作者：
Mathew AS;Gorick CM;Price RJ
背景资料：聚焦超声（FUS）血脑屏障破坏（BBBD）允许非侵入性，靶向和可重复的药物输送到大脑。FUS BBBD还激发能够增强免疫疗法、清除淀粉样蛋白-β和过度磷酸化tau并驱动神经发生的次级应答。利用这些次级效应将受益于理解它们如何与FUS BBBD的幅度相关，以及它们如何受到FUS BBBD期间施加的机械和生化刺激的不同影响。研究方法：我们在多元回归框架中聚集了75个小鼠转录组，以确定与FUS BBBD相关的生化（即对比MR图像增强（CE））或机械（即MB激活（MBA）的谐波声发射）刺激成比例表达的基因。构建模型以控制潜在混杂因素，如性别、麻醉和测序批次。结果：MBA和CE分别预测了6 h和24 h后1,124个基因的表达。虽然与MBA和CE相关的转录本存在重叠，但MBA主要预测与内皮反应性相关的基因表达，而CE主要预测无菌炎症基因集。过度代表性分析确定了先前与BBBD无关的转录本，包括肌动蛋白丝组织，这可能对BBB恢复很重要。与神经发生、小胶质细胞活化和淀粉样蛋白-β清除相关的转录物和途径与BBBD指标显著相关。结论：BBBD的次级效应可能具有通过在BBBD期间调节FUS参数来调谐的潜力，并且MBA和CE可以作为大脑中转录反应的独立预测因子。
Background: Focused ultrasound (FUS) blood brain barrier disruption (BBBD) permits the noninvasive, targeted, and repeatable delivery of drugs to the brain. FUS BBBD also elicits secondary responses capable of augmenting immunotherapies, clearing amyloid-β and hyperphosphorylated tau, and driving neurogenesis. Leveraging these secondary effects will benefit from an understanding of how they correlate to the magnitude of FUS BBBD and are differentially affected by the mechanical and biochemical stimuli imparted during FUS BBBD. Methods: We aggregated 75 murine transcriptomes in a multiple regression framework to identify genes expressed in proportion to biochemical (i.e. contrast MR image enhancement (CE)) or mechanical (i.e. harmonic acoustic emissions from MB-activation (MBA)) stimuli associated with FUS BBBD. Models were constructed to control for potential confounders, such as sex, anesthesia, and sequencing batch. Results: MBA and CE differentially predicted expression of 1,124 genes 6 h or 24 h later. While there existed overlap in the transcripts correlated with MBA vs CE, MBA was principally predictive of expression of genes associated with endothelial reactivity while CE chiefly predicted sterile inflammation gene sets. Over-representation analysis identified transcripts not previously linked to BBBD, including actin filament organization, which is likely important for BBB recovery. Transcripts and pathways associated with neurogenesis, microglial activation, and amyloid-β clearance were significantly correlated to BBBD metrics. Conclusions: The secondary effects of BBBD may have the potential to be tuned by modulating FUS parameters during BBBD, and MBA and CE may serve as independent predictors of transcriptional reactions in the brain.