Deciphering the role of Claudin-23 in regulation of the intestinal epithelial barrier

项目总结 肠上皮细胞(IECS)构成一种选择性屏障，调节营养物质的摄取和限制 抗原从管腔进入下面的粘膜。通过肠上皮的通透性是 由一系列生理和病理刺激动态调节的。慢性炎症性肠病患者 疾病(IBD)，遭受虚弱的胃肠道症状，显著影响他们的生活质量和 给医疗体系带来了不成比例的巨大经济负担。虽然遗传易感性， 环境因素和免疫失调都是IBD多因素病因的关键因素， 越来越多的证据表明肠上皮屏障功能障碍在IBD患者中起着中心作用。 肠屏障特性通过细胞间连接的动态重塑和成熟来调节 沿着IECS的侧膜。紧密连接(TJ)是最顶端的细胞间连接复合体 并由一系列高度有序的跨膜蛋白和细胞质支架蛋白组成 将复合体固定在肌动蛋白细胞骨架上。克拉丁(CLDN)家族的TJ跨膜蛋白是 由27个人体成员组成，通过调节TJ的密封性能来控制屏障功能。 在结肠中，CLDN的差异表达是为了在空间上调节屏障特性。值得注意的是，CLDN 在IBD中，表达受到干扰，并与屏障损害有关。然而，通过这些机制 IECs差异表达CLDN以控制屏障功能以及CLDN失调如何参与 IBD的上皮屏障损害仍不清楚。在这份提案中，我们提出了令人信服的初步数据 暗示CLDN23，一个未被充分研究的非古典克拉丁家族成员，是CLDN的中央管弦乐手 IECS中的络合物稳定性和TJ势垒函数。此外，我们观察到CLDN23的表达是 炎症性肠病的调节失调。因此，我提议的研究将使用新的工具来调查CLDN23是如何控制 利用体外和体内互补技术实现肠上皮屏障功能。成功完成 将扩大我们对控制肠道上皮屏障的基本机制的了解 在健康和疾病中的作用，并将为研究治疗干预措施以恢复 IBD的屏障特性和减轻炎症。重要的是，这一科学建议和培训将 为我的持久职业生涯做好准备，成为一名内科科学家，研究 胃肠道炎症性疾病。

PROJECT SUMMARY Intestinal epithelial cells (IECs) constitute a selective barrier that regulates nutrient uptake and restricts antigen access from the lumen to the underlying mucosa. Permeability across the intestinal epithelium is dynamically regulated by a range of physiologic and pathologic stimuli. Patients with chronic inflammatory bowel disease (IBD), suffer from debilitating gastrointestinal symptoms that significantly impact their quality of life and pose a disproportionately large economic burden on the healthcare system. Although genetic susceptibility, environmental factors, and immune dysregulation are all critical contributors to the multifactorial etiology of IBD, there is increasing evidence suggesting a central role for intestinal epithelial barrier dysfunction in IBD patients. Intestinal barrier properties are regulated through dynamic remodeling and maturation of intercellular junctions along the lateral membrane of IECs. Tight junctions (TJs) are the most apical intercellular junctional complex and are composed of a highly organized array of transmembrane proteins and cytoplasmic scaffolding proteins that anchor the complex to the actin cytoskeleton. The claudin (CLDN) family of TJ transmembrane proteins is comprised of 27 members in humans that control barrier function by regulating the sealing properties of the TJ. In the colon, CLDNs are differentially expressed to spatially regulate barrier properties. Notably, CLDN expression is perturbed in IBD and has been linked to barrier compromise. However, the mechanisms by which IECs differentially express CLDNs to control barrier function and how CLDN dysregulation contributes to epithelial barrier compromise in IBD remain unclear. In this proposal we present compelling preliminary data implicating CLDN23, an understudied non-classical claudin family member, as a central orchestrator of CLDN complex stability and TJ barrier function in IECs. Moreover, we have observed that CLDN23 expression is dysregulated in IBD. Thus, my proposed studies will employ novel tools to investigate how CLDN23 controls intestinal epithelial barrier function using complementary in vitro and in vivo techniques. Successful completion of the proposed studies will expand our knowledge of basic mechanisms that control intestinal epithelial barrier function in health and disease, and will open new avenues for investigation of therapeutic interventions to restore barrier properties and ameliorate inflammation in IBD. Importantly, this scientific proposal and training will position me for a sustained career as a physician-scientist studying the mechanisms of disease of gastrointestinal inflammatory illnesses.