Growth/differentiation control of keratinocytes by ROR alpha

描述(申请人提供)：分化与上皮性肿瘤的发展成反比。我们最近发现，叉头转录因子FOXN1和Notch1信号通路在功能上与抑制恶性皮肤肿瘤的形成有关。我们的工作假设是，视黄醇相关的核孤儿受体ROR1是角质形成细胞中促进分化网络的关键组成部分，作为FOXN1/Notch1基因和参与脂代谢或动态平衡的酶的上游调节因子。ROR1以前被认为与许多过程有关，包括发育、炎症和昼夜节律。我们的初步结果表明，ROR1在角质形成细胞的生长/分化和肿瘤发展中起着关键作用。在我们未来的工作中，我们将致力于以下具体目标：1)我们将以FOXN1和Notch1基因作为下游效应基因，评估ROR1是否在角质形成细胞分化的调控中发挥重要作用。我们将通过对传统和3D器官培养中的原代人类角质形成细胞(HKCs)以及ROR1基因中断的小鼠的联合分析来检验这一假设。2)我们将评估ROR1是否控制与脂代谢有关的酶的表达。我们将测试ROR1的代谢功能是否可能通过ALOXE3影响生长/分化控制和肿瘤发生的更一般方面，ALOXE3是一种与角质形成细胞分化密切相关的脂氧合酶。3)我们将评估ROR1是否在角质形成细胞肿瘤的控制中发挥重要作用。这一假设将通过遗传和药理学的双重方法进行检验。具有杂合ROR1基因突变的小鼠将被测试它们对DMBA-TPA诱导的皮肤癌的敏感性，以及具有ras癌基因表达正/负ROR1基因敲除的HKCs的异种移植肿瘤形成将被测试。在药理学方面，我们将测试用ROR1特异性激动剂(CGP52608)治疗是否可以影响化学诱导和/或异种移植瘤的形成。) 与公共健康相关：表皮分化受基因表达调控。ROR1是一种转录因子，在分化和发育过程中起着关键作用。 我们的工作假设是，ROR1通过与Notch1和FOXN1基因以及特定的脂代谢相关基因相互连接，在控制表皮分化方面发挥关键作用。)

DESCRIPTION (provided by applicant): Differentiation is inversely related to development of epithelial tumors. We recently showed that the forkhead transcription factor FOXN1 and the Notch1 signaling pathways are functionally linked to suppression of malignant skin tumor formation. Our working hypothesis is that the retinoid-related nuclear orphan receptor ROR1 is a key integral element of the pro-differentiation network in keratinocytes, functioning as an upstream regulator of FOXN1/Notch1 genes and enzymes involved in lipid metabolism or homeostasis. ROR1 has been previously implicated in a number of processes, including development, inflammation and circadian rhythm. Our preliminary results point to a key role of ROR1 in keratinocyte growth/differentiation and tumor development. For our future work we will address the following specific aims: 1) We will assess whether ROR1 plays an important role in control of keratinocyte differentiation with the FOXN1 and Notch1 genes as downstream effectors. We will test this hypothesis by a combined analysis of primary human keratinocytes (HKCs) in conventional and 3D organotypic cultures, and mice with disruption of the ROR1 gene. 2) We will assess whether ROR1 controls the expression of enzymes involved in lipid metabolism. We will test the possibility that the metabolic function of ROR1 impinges on more general aspects of growth/differentiation control and tumorigenesis via ALOXE3, a lipoxygenase that is intensively involved in keratinocyte differentiation. 3) We will assess whether ROR1 plays an important role in control of keratinocyte tumor formation. This hypothesis will be tested by a dual genetic and pharmacological approach. Mice with heterozygous ROR1 gene mutation will be tested for their sensitivity to DMBA-TPA-induced skin carcinogenesis, and xenografts of HKCs with ras oncogene expression plus/minus ROR1 knockdown will be tested for tumor formation. Pharmacologically, we will test whether treatment with a ROR1 specific agonist (CGP 52608) can affect chemical- induced and/or xenograft tumor formation. ) PUBLIC HEALTH RELEVANCE: Epidermal differentiation is regulated by orchestrated gene expression. ROR1 is a transcription factor with a critical role in differentiation and development. Our working hypothesis is that ROR1 plays a key role in control of epidermal differentiation through an interconnection with the Notch1 and FOXN1 genes and with specific lipid metabolism related genes.)