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

基本信息

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
项目类别：
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

项目摘要

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运输界面。随着中胚层衍生的脉管系统侵入未成熟的中枢神经系统（CNS），BBB在胚胎发育的早期开始形成，并开始获得BBB特征，例如紧密连接和缺乏Fenestrae。进一步成熟后，成年BBB具有非常低的渗透性和大量分子运输系统，可以通过与神经血管单元的支持细胞相互作用来维持。虽然最近的研究表明Wnt/β-蛋白蛋白，血管紧张素II和Sonic刺猬信号在BBB发育中的重要性，但当这些途径被破坏时，许多BBB属性仍未受到影响。因此，我们对基于BBB形成的分子机制的理解是不完整的，在此提案中，我们旨在进一步研究调节BBB发育和维持的机制。最近，我们将核受体rxralpha和ppardelta确定为BBB功能的两个潜在调节剂。如初步数据中所述，与周围内皮的受体激动剂相比，这些受体在BBB上特异性表达，可以驱动与人多能干细胞（HPSC衍生的BMEC）和内皮特异性缺失的内皮细胞中BBB表型的驱动。导致部分新生儿致死性（Rxralpha）和体内漏水的BBB（Ppardelta）。因此，我们假设核受体rxralpha和ppardelta是BBB发育和维持的关键调节剂。为了检验我们的假设，我们将评估小鼠rxralpha和ppardelta的胚胎和产后内皮特异性缺失后体内BBB表型。由Rxralpha和Ppardelta激活控制的分子机制将使用HPSC衍生的BMEC的分化过程进行评估，以作为人类BBB诱导和维持的窗口。最后，将在体内和体外评估由rxralpha和ppardelta共激活引起的BBB形成的潜在协同作用。了解BBB诱导的调节剂可能会产生有关胎儿脑疾病的许多新见解。此外，对障碍生成和障碍维护途径的了解可能会为恢复BBB功能的新途径在使神经系统疾病的衰弱中恢复。