The Lipid and Tight Junction Epidermal Barriers are Interdependent

描述(申请人提供)：假设：先前的研究表明紧密连接(TJ)蛋白对子宫内表皮通透性屏障的形成至关重要，但 TJ及其组成蛋白在出生后表皮中的功能尚不清楚。我们发现哺乳动物表皮TJ的表达和功能在表皮发育过程中发生了变化。因此，我们假设TJ和角质层脂屏障具有不同的功能，但相互依赖。建议工作描述：我们最新的研究表明，TJ和由脂质分泌和加工形成的角质层屏障在表皮通透性发育中起互补作用。我们发现，与其他致密上皮相似，缺水的TJ首先在表皮发育过程中形成，但这些TJ失去了阻止水和离子的能力。在R21提案中，随着脂质屏障的形成，我们将测试表皮TJ的表达是否因脂质屏障功能而改变。目的#1将评估脂质屏障的变化如何控制TJ在产前和围产期表皮发育中的表达和功能。目的#2测试TJ的表达是否能保护表皮免受金黄色葡萄球菌(SA)的侵袭。这些实验将为以后R01提案的影响奠定基础：虽然许多实验室正在研究TJ或表皮中的脂质屏障，但到目前为止，还没有研究集中在这些互补屏障之间的关系。此外，这些屏障之间的关系可能会对产前、早产儿和新生儿皮肤抵抗细菌感染的能力产生深远影响。因此，这项研究可能会对研究表皮发育和对细菌感染的反应产生持续而强大的影响。

DESCRIPTION (provided by applicant): Hypothesis: Prior studies have shown that tight junctions (TJ) proteins are critical for epidermal permeability barrier formation in utero, but the function of TJ and their constituent proteins in postnatal epidermis is unknown. We find that the expression and function of mammalian epidermal TJ change during epidermal development. Therefore, we hypothesize that the TJ and stratum corneum lipid barriers subserve different functions, but are interdependent. Description of proposed work: Our most recent research suggests that TJ and the stratum corneum barrier formed by lipid secretion and processing serve complementary roles in epidermal permeability development. We find that water-impermeant TJ, similar to those in other tight epithelia, are formed first during epidermal development, but these TJ lose their ability to block water and ions as the lipid barrier is formed In this R21 proposal, we will test whether epidermal TJ expression is modified in response to lipid barrier function. Aim #1 will assess how changes in the lipid barrier control TJ expression and function in prenatal and perinatal epidermal development. Aim #2 will test whether TJ expression protects the epidermis from Staphylococcus aureus (SA) invasion. These experiments will form the basis for a later R01 proposal Impact: While many laboratories are studying TJ or the lipid barrier in the epidermis, to date no studies have focused on the relationship between these complementary barriers. Moreover, the relationship between these barriers may have a profound effect on the ability of prenatal, premature, and neonatal skin to resist bacterial infection. Thus, this research is likely to exert a sustained, powerful influence n the research studying epidermal development and responses to bacterial infection.