ONTOGENY OF THE PERMEABILITY BARRIER

描述：(改编自申请人的摘要)-经过改进 早产儿存活、角质层未成熟(SC) 皮肤屏障功能不全已成为 发病率。这位研究人员最近证明了几种配体 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， 因为干细胞的发育在胎儿皮肤器官培养中正常进行 激素缺乏和体内面对糖皮质激素或甲状腺激素 激素缺乏症申请者假设胎儿干细胞发育可能 也可被当地产生的核激素受体配体激活。 最近，他们发现PPARpha(激活剂-脂肪)的激活剂 酸)或FXR(激活剂-法尼醇，一种源自中间体的异戊二烯 在胆固醇生物合成途径中)加速胎儿表皮和SC 发展。胎儿表皮是一种非常活跃的脂肪酸和 胆固醇的合成，因此这两种核激素受体 配体/激活剂是在当地产生的，因此可以调节SC 发展。PPARpha和FXR都是RXR子组的成员 核激素受体，还包括RXR、RAR和维生素D 受体。鉴于核受体在细胞内的重要调节作用 皮肤：PPARpha和FXR很可能也将发挥关键作用 在表皮生理学方面。 假说：胚胎发育过程中SC的形成和一种有效的屏障 发育需要产生富含细胞外脂肪的 板层膜和角化的包膜，两者都是受调节的 通过激活PPARpha和/或FXR核受体。 具体目标：1)确定PPARpha和FXR激活剂是否加速 胚胎干细胞在子宫内和早产后的发育。2)澄清 促进SC个体发育的基础研究人员将 确定PPARpha和/或FXR激活剂是否会增加表达和/或 SC形成所需的关键酶和结构蛋白的活性。 3)确定PPARpha和/或FXR是否是关键的信号蛋白 它规定了SC/渗透性屏障的发展时间表。

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.