Role of RORa in Epidermal Differentiation Control

描述(申请人提供)：皮肤动态平衡是通过精确控制的表皮生长和分化实现的，这是由一个集成的信号网络调节的。阐明该网络中的通路如何相互协调以维持增殖和分化之间的平衡，将有助于我们了解皮肤生理学和病理学。视黄醇相关的孤儿受体ROR1是多种组织分化和发育的关键因子，也参与钙信号和昼夜节律。我们的初步发现表明，在原代人类角质形成细胞(HKCs)中，ROR1的表达被诱导分化，而在鳞状细胞癌(SCC)中则不表达。增加ROR1的表达足以诱导角质形成细胞分化标志物的表达，而抑制ROR1的表达则具有相反的作用。此外，在Notch1基因的启动子区域存在多个ROR1结合元件，它是角质形成细胞进入分化的直接决定因素，ROR1表达增加可以调节Notch1的转录和Notch活性。因此，我们假设ROR1通过与Notch信号的相互连接在控制表皮分化中发挥关键作用。为了验证这一假设，我们将首先检测ROR1表达的增加和减少对人原代角质形成细胞(HKCs)增殖和分化的影响。同时，我们将对ROR1缺失小鼠的皮肤进行组织学和生化分析，以更确凿地确定ROR1在控制表皮增殖和分化中的作用。在这些研究之后，将对ROR1和Notch信号通路之间的相互调制进行机制描述。这项研究的结果将为皮肤生物学提供基本的见解，并可能直接关系到开发各种皮肤病的新疗法。 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Notch信号相互连接，在控制表皮分化方面发挥关键作用。

DESCRIPTION (provided by applicant): Skin homeostasis is achieved through precisely controlled epidermal growth and differentiation, which are regulated by an integrated signaling network. Elucidation of how the pathways within the network coordinate with each other to maintain the balance between proliferation and differentiation will contribute to our knowledge of skin physiology and pathology. The retinoid-related orphan receptor ROR1 is a critical factor in differentiation and development of several tissues, and it is also involved in calcium signaling and circadian rhythm. Our preliminary findings indicate that ROR1 expression is induced with differentiation in primary human keratinocytes (HKCs) and is absent in squamous cell carcinoma (SCC). Increased ROR1 expression is sufficient to induce expression of keratinocyte differentiation markers, while suppression of ROR1 has the opposite effect. Moreover, there are several ROR1 binding elements present in the promoter region of Notch1 gene, which is a direct determinant of keratinocyte entry into differentiation, and increased ROR1 expression could modulate Notch1 transcription and Notch activity. We therefore hypothesize that ROR1 plays a key role in control of epidermal differentiation through an interconnection with Notch signaling. To test this hypothesis, we will first examine the impact of increased and reduced ROR1 expression on proliferation and differentiation of human primary keratinocytes (HKCs). In parallel, we will perform histological and biochemical analysis of skin derived from ROR1 null mice to more conclusively establish the role of ROR1 in epidermal proliferation and differentiation control. These studies will be followed by a mechanistic characterization of the reciprocal modulation between ROR1 and the Notch signaling pathway. The results from this study will provide fundamental insight into skin biology and may have direct bearing on developing new treatment for various skin diseases. 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 Notch signaling.