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

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
批准号:
10440912
负责人:
Bethany E Perez White
金额:
$6.29万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-08-01 至 2022-07-31

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中文摘要
翻译
Perez White, Bethany 5K01AR072773-03行政补充请求
英文摘要
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.
期刊论文(2)
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会议论文
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: Experimental dermatology
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
Skin Tissue Engineering
  • 批准号:
    9117969
  • 项目类别:
  • 资助金额:
    $25.35万
  • 财政年份:
    2016
  • 负责人:
    Bethany E Perez White
  • 依托单位:
海外基金