ONTOGENY OF THE PERMEABILITY BARRIER

描述：（改编自申请人的摘要）-改进的 早产儿存活率、角质层（SC）不成熟 皮肤屏障功能不全的患者， 发病率 研究人员最近表明， 核受体超家族中的受体（例如，糖皮质激素， 甲状腺激素）是胎儿SC发育的重要调节因子。 然而，在这方面， 因为SC发育在胎儿皮肤器官培养中正常进行， 缺乏激素和在体内面对糖皮质激素或甲状腺 激素缺乏，申请人假设胎儿SC发育可能 也可被局部产生的核激素受体配体激活。 最近，他们已经表明，PPARalpha的激活剂（激活剂-脂肪酸）， 酸）或FXR（活化剂-法尼醇，一种衍生自中间体的类异戊二烯 在胆固醇生物合成途径）加速胎儿表皮和SC 发展 胎儿表皮是一个非常活跃的脂肪酸和 胆固醇合成，因此这两种核激素受体 局部产生配体/激活剂，从而可以调节SC 发展 PPARalpha和FXR都是RXR亚组的成员， 核激素受体，还包括RXR，RAR和维生素D 受体的 鉴于核受体在细胞内的重要调节作用， 在皮肤中，PPARalpha和FXR也可能发挥关键作用， 在表皮生理学上。 假设：胎儿期SC和有效屏障的形成 发育需要产生细胞外富含脂质的 板层膜和皮质包膜，两者都受到调节 通过激活PPAR α和/或FXR核受体。 具体目的：1）确定PPARalpha和FXR激活剂是否加速 SC在子宫内和早产后的发育。 2)阐明本 加速SC个体发育的基础，研究人员将 确定PPARalpha和/或FXR激活剂是否增加表达和/或 SC形成所需的关键酶和结构蛋白的活性。 3)确定PPARalpha和/或FXR是否是关键的信号蛋白， 其规定了SC/渗透性屏障的开发时间表。

DESCRIPTION: (Adapted from the applicant's abstract) - With improved survival of the premature infant, immaturity of the stratum corneum (SC) with an incompetent cutaneous barrier has become a major source of morbidity. The investigator has recently shown that ligands of several receptors in the nuclear receptor superfamily (for example, glucocorticoids, thyroid hormone) are important regulators of fetal SC development. However, because SC development proceeds normally in fetal skin organ cultures in the absence of hormones and in vivo in the face of glucocorticoid or thyroid hormone deficiency the applicants hypothesized that fetal SC development may also be activated by locally generated ligands of nuclear hormone receptors. Recently, they have shown that activators of PPARalpha (activator-fatty acids) or FXR (activator-farnesol, an isoprenoid derived from intermediates in the cholesterol biosynthetic pathway) accelerate fetal epidermal and SC development. Fetal epidermis is a very active site of both fatty acid and cholesterol synthesis, and therefore both of these nuclear hormone receptor ligands/activators are produced locally and thereby could modulate SC development. Both PPARalpha and FXR are members of the RXR subgroup of nuclear hormones receptors which also includes RXR, RAR, and Vitamin D receptor. Given the important regulatory role of nuclear receptors in the skin it is likely that both PPARalpha and FXR will also have crucial roles in epidermal physiology. Hypothesis: Formation of the SC and a competent barrier during fetal development requires both the generation of extracellular lipid-enriched lamellar membranes and the cornified envelope, both of which are regulated by activation of PPARalpha and/or FXR nuclear receptors. Specific Aims: 1) To determine if PPARalpha and FXR activators accelerate SC development in utero and following premature birth. 2) To elucidate the basis for the acceleration of SC ontogenesis the investigators will determine if PPARalpha and/or FXR activators increase the expression and/or activity of key enzymes and structural proteins required for SC formation. 3) To determine if PPARalpha and/or FXR are the crucial signaling proteins that regulate the timetable of development of the SC/permeability barrier.