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首页> 外文学位 >Endothelial Wnt/beta-catenin modulates blood-brain barrier integrity in a mouse model of multiple sclerosis.
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Endothelial Wnt/beta-catenin modulates blood-brain barrier integrity in a mouse model of multiple sclerosis.

机译：内皮Wnt /β-连环蛋白调节多发性硬化小鼠模型中的血脑屏障完整性。

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摘要

Blood-brain barrier (BBB) breakdown is a contributing factor in many neurological diseases, including Multiple Sclerosis (MS). MS is an inflammatory disease in which auto-reactive T-cells become activated towards myelin, infiltrate into the CNS, and mediate myelin and eventually neuronal destruction. The majority of patients have MS manifest as a relapsing-remitting type, in which there is a flare-up of symptoms as CNS inflammatory infiltration and damage occur, followed by the subsiding of symptoms. It is known the BBB is degraded before relapses resulting in symptoms and is subsequently repaired during the remission phase. However, it is still not known what pathways mediate the repair of the BBB in the remission phase. The Wnt/beta-catenin pathway controls development of the BBB; however its role in repairing the BBB in diseases where it is impaired remains unclear. The focus of this research was to investigate whether the Wnt/beta-catenin pathway is active during a mouse model of MS and elucidate the role that this pathway might play on endothelial barrier properties and immune cell infiltration in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). I demonstrate that the Wnt/beta-catenin pathway is upregulated in CNS endothelial cells during EAE progression and genetic ablation of Wnt/beta-catenin activity in endothelial cells exacerbated EAE clinical presentation, immune cell infiltration, demyelination and enhances vascular expression of the adhesion molecule VCAM1 and the transcytosis protein Caveolin-1, without affecting tight junction proteins (Chapter 3). Chemical activation of the Wnt/beta-catenin pathway during EAE was unsuccessful and failed to alter EAE clinical disease course (Chapter 4). Lastly, I provide evidence that the Wnt/beta-catenin pathway is highly upregulated in ECs within MS lesions, paralleling my findings in the EAE mouse model (Chapter 5). This study opens the possibility to develop a new target for therapeutics that can enhance BBB integrity during MS.
机译：血脑屏障（BBB）破坏是许多神经系统疾病（包括多发性硬化症（MS））的促成因素。 MS是一种炎症性疾病，其中自反应性T细胞被激活并朝向髓磷脂，渗透到CNS中，并介导髓磷脂并最终介导神经元破坏。大多数患者的MS表现为复发缓解型，其中出现中枢神经系统炎性浸润和损害，症状随之发作，随后症状消失。众所周知，血脑屏障在复发之前会降解，导致症状，然后在缓解阶段进行修复。然而，仍不清楚在缓解期中有哪些途径介导了血脑屏障的修复。 Wnt /β-catenin途径控制BBB的发育；然而，其在受损的血脑屏障中修复血脑屏障的作用尚不清楚。这项研究的重点是研究Wnt /β-catenin途径在MS小鼠模型中是否活跃，并阐明该途径可能在MS小鼠模型（实验性自身免疫）中对内皮屏障特性和免疫细胞浸润的作用。脑脊髓炎（EAE）。我证明了在EAE进展过程中CNS内皮细胞中Wnt /β-catenin途径上调，并且内皮细胞中Wnt /β-catenin活性的遗传消融加剧了EAE临床表现，免疫细胞浸润，脱髓鞘并增强了粘附分子的血管表达VCAM1和转胞吞蛋白Caveolin-1，而不会影响紧密连接蛋白（第3章）。 EAE期间Wnt /β-catenin途径的化学激活未成功，并且未能改变EAE临床疾病进程（第4章）。最后，我提供证据表明Wnt /β-catenin途径在MS病变内的EC中高度上调，与我在EAE小鼠模型中的发现相似（第5章）。这项研究为开发新的治疗靶标提供了可能性，该靶标可增强MS期间BBB的完整性。

著录项

  • 作者

    Lengfeld, Justin Edward.;

  • 作者单位

    University of California, Irvine.;

  • 授予单位 University of California, Irvine.;
  • 学科 Cellular biology.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 200 p.
  • 总页数 200
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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