Effects of Psychological Stress on the Stratum Corneum

描述(由申请人提供)： 虽然心理应激(PS)是公认的引起和加重皮肤病的因素，但其机制(S)尚不清楚。最近，我们在PS动物模型和人类PS模型中发现通透性屏障动态平衡受损。PS可增加血清糖皮质激素(GC)水平，抑制GC作用可防止屏障异常。此外，GC处理同样由于减少板层小体(LB)的产生和分泌而导致屏障功能异常，这可以通过GC抑制表皮胆固醇、脂肪酸和神经酰胺的合成来解释。外用脂类可直接纠正屏障异常，说明表皮脂质合成受抑是屏障异常的主要原因。GC治疗也损害了SC的完整性和凝聚力，原因是皮质桥粒(CD)密度降低。局部脂质改善了SC完整性和凝聚力的缺陷，表明脂质缺乏也在调节这些异常中发挥作用。假设：PS通过刺激GC的产生抑制屏障动态平衡，后者抑制表皮脂的合成，导致LB的形成/分泌减少，从而损害屏障动态平衡。此外，PS/GC诱导的SC中板层膜的减少增加了蛋白酶活性，降低了Cd密度，从而降低了SC的完整性和内聚力。纠正脂质缺乏可以减轻PS和GC治疗对表皮的有害后果。目的1-确定PS是否通过增加GC的产生，a)通过减少表皮脂质的合成和LB的形成/分泌来破坏屏障动态平衡，以及b)通过降低SC中的Cd浓度来损害SC的完整性和凝聚力。目的2-确定PS/GC抑制表皮脂肪合成的生化基础和分子机制。目的3-为了确定SC完整性和凝聚力异常的机制，我们将评估PS/GC对Cd的形成和降解的影响。目的：探讨GC对人皮肤通透性屏障动态平衡和SC完整性/内聚性的影响是否与表皮脂质合成受到抑制有关。

DESCRIPTION (provided by applicant): Although psychological stress (PS) is well recognized to provoke and exacerbate cutaneous disorders the mechanism(s) for this are unknown. Recently, we have shown that permeability barrier homeostasis is impaired in animal models of PS and in humans with PS. PS increases serum glucocorticoid (GC) levels and inhibition of GC action prevents the barrier abnormality. Moreover, GC treatment similarly produces an abnormality in barrier function due to the decreased production and secretion of lamellar bodies (LB), which can be explained by GC inhibiting the epidermal synthesis of cholesterol, fatty acids, and ceramides. Topical lipids correct the barrier abnormality directly demonstrating that the inhibition of epidermal lipid synthesis is a major factor accounting for the abnormal barrier. GC treatment also compromises SC integrity and cohesion due to a decrease corneodesmosomes (CD) density. Topical lipids improve the defect in SC integrity and cohesion indicating that a deficiency of lipids also plays a role in mediating these abnormalities. Hypothesis: PS inhibits barrier homeostasis by stimulating GC production, which inhibits epidermal lipid synthesis resulting in a decrease in LB formation/secretion leading to impaired barrier homeostasis. Additionally, the PS/GC induced decrease in lamellar membranes in the SC increases protease activity reducing CD density, thereby decreasing SC integrity and cohesion. Correction of the lipid deficiency ameliorates the harmful consequences of PS and GC treatment on the epidermis. Aim 1- To determine if PS, by increasing GC production, a) impairs barrier homeostasis by decreasing epidermal lipid synthesis and LB formation/ secretion and b) compromises SC integrity and cohesion by decreasing CD density in the SC. Aim 2- To determine the biochemical basis and molecular mechanisms responsible for the PS/GC induced inhibition of epidermal lipid synthesis. Aim 3-To determine the mechanisms for the abnormality in SC integrity and cohesion, we will assess the effects of PS/GC on both the formation and degradation of CD. Aim 4: To determine if the abnormalities in permeability barrier homeostasis and SC integrity/ cohesion induced by GC treatment in humans, are due to the inhibition of epidermal lipid synthesis.