RXRalpha and PPARdelta Signaling as Novel Regulators of the Blood-Brain Barrier

RXRalpha 和 PPARdelta 信号作为血脑屏障的新型调节剂

• 批准号: 8660105
• 负责人: ERIC V SHUSTA
• 金额: $ 38.12万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660105
• 关键词: Adult; Affect; Agonist; Angiotensin II; Astrocytes; Biological Models; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; Brain Diseases; Cell Culture Techniques; Cell model; Characteristics; Cues; Data; Development; Developmental Process; Disease; Embryo; Embryonic Development; Endothelial Cells; Endothelium; Functional disorder; Gene Expression; Gene Expression Profiling; Genetic; Genetic Transcription; Heterodimerization; Heterozygote; Homeostasis; Human; In Vitro; Invaded; Knockout Mice; Knowledge; Liver; Lung; Maintenance; Mesoderm; Modeling; Molecular; Monitor; Multiple Sclerosis; Mus; Mutant Strains Mice; Neonatal; Neuraxis; Neurons; Nuclear Receptors; PPAR delta; Pathology; Pathway interactions; Patients; Pericytes; Peripheral; Permeability; Phase; Phenotype; Play; Pluripotent Stem Cells; Process; Property; Receptor Signaling; Regulation; Research; Role; Signal Pathway; Signal Transduction; Stroke; Supporting Cell; System; Tamoxifen; Testing; Tight Junctions; Transport Process; Undifferentiated; Work; beta catenin; cell type; fetal; genetic analysis; in vivo; insight; mouse model; nerve stem cell; nervous system disorder; neurovascular unit; novel; postnatal; programs; public health relevance; receptor; restoration; smoothened signaling pathway

DESCRIPTION (provided by applicant): The blood-brain barrier (BBB) acts as a signaling and transport interface between the blood and brain. The BBB begins to form early in embryonic development as the mesoderm-derived vasculature invades the immature central nervous system (CNS) and begins to gain BBB characteristics such as tight junctions and a lack of fenestrae. After further maturation, the adult BBB, with its very low permeability and a wealth of molecular transport systems, is maintained by interactions with supporting cells of the neurovascular unit. While recent studies have indicated the importance of Wnt/beta- catenin, angiotensin II, and sonic hedgehog signaling on BBB development, many BBB attributes remain unaffected when these pathways are disrupted. Thus, our understanding of the molecular mechanisms underpinning BBB formation is incomplete, and in this proposal we aim to further examine the mechanisms that regulate BBB development and maintenance. Recently, we have identified nuclear receptors RXRalpha and PPARdelta as two potential regulators of BBB function. As described in the preliminary data, these receptors are specifically expressed at the BBB compared to peripheral endothelia, receptor agonists can drive BBB phenotypes in endothelial cells differentiated from human pluripotent stem cells (hPSC-derived BMECs), and endothelial-specific deletion of these receptors results in partial neonatal lethality (RXRalpha) and a leaky BBB (PPARdelta) in vivo. Thus, we hypothesize that the nuclear receptors RXRalpha and PPARdelta are crucial regulators of BBB development and maintenance. To test our hypothesis, we will evaluate the in vivo BBB phenotype upon embryonic and postnatal endothelial-specific deletion of RXRalpha and PPARdelta in mice. The molecular mechanisms governed by RXRalpha and PPARdelta activation will be evaluated using the differentiation process of hPSC-derived BMECs as a window to human BBB induction and maintenance. Finally, potential synergy on BBB formation arising from RXRalpha and PPARdelta co-activation will be assessed in vivo and in vitro. Understanding the regulators of BBB induction could yield many new insights regarding fetal brain disease. Furthermore, knowledge of the barrier-genesis and barrier maintenance pathways could open new avenues for restoring BBB function in debilitating neurological disease.

描述（由申请人提供）：血脑屏障（BBB）充当血液和大脑之间的信号传导和传输界面。当中胚层衍生的脉管系统侵入未成熟的中枢神经系统（CNS）并开始获得 BBB 特征（例如紧密连接和缺乏窗孔）时，BBB 在胚胎发育早期开始形成。进一步成熟后，成人血脑屏障具有非常低的渗透性和丰富的分子运输系统，通过与神经血管单元的支持细胞的相互作用来维持。虽然最近的研究表明 Wnt/β-连环蛋白、血管紧张素 II 和声波刺猬信号对 BBB 发育的重要性，但当这些途径被破坏时，许多 BBB 属性仍然不受影响。因此，我们对 BBB 形成的分子机制的理解并不完整，在本提案中，我们的目标是进一步研究调节 BBB 发育和维持的机制。最近，我们发现核受体 RXRα 和 PPARδ 是 BBB 功能的两个潜在调节因子。如初步数据所述，与外周内皮细胞相比，这些受体在 BBB 上特异性表达，受体激动剂可以驱动从人多能干细胞（hPSC 衍生的 BMEC）分化的内皮细胞中的 BBB 表型，这些受体的内皮特异性缺失会导致部分新生儿致死 (RXRalpha) 和血脑屏障渗漏 （PPARδ）体内。因此，我们假设核受体 RXRα 和 PPARδ 是 BBB 发育和维持的关键调节因子。为了检验我们的假设，我们将评估小鼠胚胎和出生后内皮特异性 RXRα 和 PPARδ 缺失后的体内 BBB 表型。将使用 hPSC 衍生的 BMEC 的分化过程作为人类 BBB 诱导和维持的窗口来评估 RXRα 和 PPARδ 激活控制的分子机制。最后，将在体内和体外评估 RXRα 和 PPARδ 共激活对 BBB 形成的潜在协同作用。了解 BBB 诱导的调节因素可能会产生许多关于胎儿脑部疾病的新见解。此外，对屏障发生和屏障维持途径的了解可以为恢复衰弱性神经系统疾病中的血脑屏障功能开辟新途径。