Effects of Psychological Stress on the Stratum Corneum

描述（由申请人提供）： 虽然心理应激（PS）被公认为引起和加重皮肤疾病，但其机制尚不清楚。最近，我们已经表明，在PS动物模型和PS患者中，渗透屏障稳态受损。PS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治疗类似地由于板层体（LB）的产生和分泌减少而产生屏障功能异常，这可以通过GC抑制胆固醇、脂肪酸和神经酰胺的表皮合成来解释。局部脂质直接纠正屏障异常，表明表皮脂质合成的抑制是导致屏障异常的主要因素。GC处理还由于角蛋白桥粒（CD）密度降低而损害SC完整性和凝聚力。局部脂质改善了SC完整性和凝聚力的缺陷，表明脂质的缺乏也在介导这些异常中起作用。假设：PS通过刺激GC产生来抑制屏障稳态，GC抑制表皮脂质合成，导致LB形成/分泌减少，从而导致屏障稳态受损。此外，PS/GC诱导的SC中层状膜的减少增加了蛋白酶活性，降低了CD密度，从而降低了SC的完整性和凝聚力。脂质缺乏的纠正改善了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产生，a）通过减少表皮脂质合成和LB形成/分泌损害屏障稳态，和B）通过降低SC中的CD密度损害SC完整性和凝聚力。目的2-确定负责PS/GC诱导的表皮脂质合成抑制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形成和降解的影响。目标4：确定GC处理诱导的人体渗透性屏障稳态和SC完整性/凝聚力异常是否是由于抑制表皮脂质合成所致。

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.