Breaking down barriers: defining the role of EphA2 in building epidermal tight junctions in atopic dermatitis

打破障碍:定义 EphA2 在特应性皮炎中建立表皮紧密连接中的作用

基本信息

项目摘要

Perez White, Bethany 5K01AR072773-03 Administrative Supplement Request PROJECT SUMMARY Tight junctions are a vital component of the epidermal barrier and are required for skin function. While we know these structures are disrupted in skin diseases such as atopic dermatitis (AD), we do not fully understand the normal signaling contributing to their function. This knowledge gap makes finding therapies to restore tight junction activity difficult. Therefore, defining the signaling pathways responsible for establishing tight junctions would serve not only to advance our basic understanding of skin biology, but also may provide leads for drug targeting and disease intervention. Our preliminary evidence indicates that EphA2 receptor tyrosine kinase (RTK) contributes to the formation and function of tight junctions in 2D cultures. Genetic manipulation of these cultures to remove EphA2 results in a loss of the localization of tight junction proteins from the stratum granulosum in which they reside. In addition, we have found a loss of tight junction function by measuring electrical resistance and the permeability of large molecules in 2D keratinocyte cultures. Based on these changes in epidermal integrity after loss of EphA2, we hypothesize that EphA2 is a positive regulator of tight junctions in the epidermis and can be targeted to improve tight junction barrier function. We specifically will determine how EphA2 is regulating tight junctions and if EphA2 could be targeted pharmacologically to enhance skin barrier function. Our initial studies implicate the structural protein afadin, downstream of EphA2 signaling, as a positive regulator of the formation and function of tight junctions in epidermal keratinocytes. Our studies have found that EphA2 loss leads to the mislocalization of afadin from cell borders to the cell's interior regions, and a loss in afadin and tight junction proteins. Therefore, we will first test the effect of EphA2 and afadin loss on the assembly and functionality of tight junctions in 3D reconstituted human epidermis (3D RHE). We will next test the mechanism by which EphA2 alters afadin expression, leading to tight junction defects. We have also uncovered novel EphA2/EGFR RTK crosstalk that is integral to TJ morphogenesis. Finally, we will use 3D RHE and animal models of AD to determine if EphA2 ligand activation with ephrin-A1 can enhance tight junction barrier function and either prevent or reverse the manifestations of this disease. AD is a prevalent skin disease primarily affecting infants and young children characterized by an epidermal barrier defect in association with skin inflammation. This chronic condition severely decreases the quality of life of patients and their families, and causes a significant lifelong economic burden. By understanding the biology of tight junctions, a critical structural component of the skin that is dysfunctional in AD, we can seek new therapies to alleviate this disease. We have proposed that the EphA2/ephrin-A1 signaling axis can be harnessed to normalize tight junction defects in AD.
佩雷斯·怀特,贝萨尼5K01AR072773-03行政补充申请 项目总结 紧密连接是表皮屏障的重要组成部分,是皮肤功能所必需的。虽然我们知道 这些结构在特应性皮炎(AD)等皮肤病中被破坏,我们还不完全了解 正常的信号对它们的功能起作用。这一知识差距使寻找治疗方法变得紧张 交界处活动困难。因此,定义负责建立紧密连接的信号通路 这不仅有助于增进我们对皮肤生物学的基本了解,还可能为药物提供线索 针对性和疾病干预。我们的初步证据表明,EphA2受体酪氨酸激酶 (RTK)有助于2D培养中紧密连接的形成和功能。对这些基因的操纵 去除EphA2的培养会导致地层中紧密连接蛋白的定位丢失 它们所居住的颗粒层。此外,我们还通过测量发现了紧密连接功能的损失 2D角质形成细胞培养中大分子的电阻和通透性。基于这些 失去EphA2后表皮完整性的变化,我们假设EphA2是一种正向调节因子 可针对表皮中的紧密连接和改善紧密连接屏障功能。我们 具体将确定EphA2是如何调节紧密连接的,以及EphA2是否可以成为靶点 具有增强皮肤屏障功能的药理作用。我们的初步研究涉及结构蛋白afadin, EphA2信号的下游,作为紧密连接的形成和功能的正向调节因子 表皮角质形成细胞。我们的研究发现,EphA2的缺失导致了afadin的错误定位 细胞与细胞内部区域接壤,并且失去了afadin和紧密连接蛋白。因此,我们将首先 检测EphA2和afadin丢失对三维重组紧密连接组装和功能的影响 人体表皮(3D RHE)。接下来我们将测试EphA2改变afadin表达的机制, 导致紧密结缺陷。我们还发现了新的EphA2/EGFR RTK串扰,它是 TJ形态发生。最后,我们将使用3D RHE和AD的动物模型来确定EphA2配体是否 用ephin-A1激活可增强紧密连接屏障功能,防止或逆转 这种疾病的表现。AD是一种流行的皮肤病,主要影响婴幼儿 以与皮肤发炎相关的表皮屏障缺陷为特征。这种慢性病 严重降低了患者及其家人的生活质量,并造成了巨大的终身经济损失 负担。通过了解紧密连接的生物学,皮肤的一个关键结构成分 在AD功能障碍的情况下,我们可以寻求新的治疗方法来缓解这种疾病。我们已建议 EphA2/ePhin-A1信号轴可以被用来正常化AD的紧密连接缺陷。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Gene expression profiling of laminin α3-blocked keratinocytes reveals an immune-independent mechanism of blistering.
层粘连蛋白α3阻断角质形成细胞的基因表达分析揭示了一种免疫依赖性的泡沫机制。
  • DOI:
    10.1111/exd.14501
  • 发表时间:
    2022-04
  • 期刊:
  • 影响因子:
    3.6
  • 作者:
    Bao L;Perez White BE;Li J;Patel PM;Amber KT
  • 通讯作者:
    Amber KT
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Bethany E Perez White其他文献

Bethany E Perez White的其他文献

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{{ truncateString('Bethany E Perez White', 18)}}的其他基金

Skin Tissue Engineering
皮肤组织工程
  • 批准号:
    9117969
  • 财政年份:
    2016
  • 资助金额:
    $ 6.29万
  • 项目类别:

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