ONTOGENY OF THE PERMEABILITY BARRIER

渗透屏障的个体发育

• 批准号: 2628388
• 负责人: MARY L WILLIAMS
• 金额: $ 22.54万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-15 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2628388
• 关键词: cholesterol; electron microscopy; embryo /fetus; embryo /fetus tissue /cell culture; enzyme activity; enzyme mechanism; epidermal growth factor; fatty acid biosynthesis; fatty acid synthase; histogenesis; hormone receptor; hormone regulation /control mechanism; isoprenoid; keratinocyte; laboratory mouse; laboratory rat; lipid biosynthesis; membrane permeability; skin; steroid hormone; thyroid hormones; tissue /cell culture; vitamin D receptors

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.

描述：（改编自申请人的摘要）- 改进 早产儿的存活，角质层的不成熟（SC） 皮肤屏障功能不全已成为主要来源 发病率。 研究人员最近表明，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 SC 发育在胎儿皮肤器官培养中正常进行 缺乏激素和体内面临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 也可以被局部产生的核激素受体配体激活。 最近，他们发现 PPARα 激活剂（激活剂-脂肪 酸）或 FXR（激活剂法尼醇，一种从中间体衍生的类异戊二烯 在胆固醇生物合成途径中）加速胎儿表皮和 SC 发展。 胎儿表皮是脂肪酸和脂肪酸非常活跃的部位 胆固醇合成，因此这两种核激素受体 配体/激活剂是局部产生的，因此可以调节 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。 鉴于核受体在细胞核中的重要调节作用 PPARalpha 和 FXR 很可能在皮肤中也发挥着至关重要的作用 在表皮生理学中。 假设：SC 的形成和胎儿期的有效屏障 发育需要产生富含细胞外脂质的物质 层状膜和角化膜，两者均受到调节 通过激活 PPARα 和/或 FXR 核受体。 具体目标：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 研究人员将作为加速 SC 个体发生的基础 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 PPARα 和/或 FXR 是否是关键的信号蛋白 规范 SC/渗透屏障的开发时间表。