Role of RORa in Epidermal Differentiation Control

描述（由申请人提供）：皮肤稳态是通过精确控制表皮生长和分化来实现的，这是由一个综合信号网络调节的。阐明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。类维甲酸相关孤儿受体ROR1是多种组织分化和发育的关键因子，也参与钙信号传导和昼夜节律。我们的初步研究结果表明，ROR1的表达在原代人角质形成细胞（HKCs）中受分化诱导，而在鳞状细胞癌（SCC）中不存在。ROR1表达的增加足以诱导角质细胞分化标志物的表达，而ROR1的抑制则具有相反的作用。此外，在Notch1基因的启动子区域存在多个ROR1结合元件，这是角质形成细胞进入分化的直接决定因素，ROR1表达的增加可以调节Notch1的转录和Notch活性。因此，我们假设ROR1通过与Notch信号的互连在控制表皮分化中起关键作用。为了验证这一假设，我们将首先研究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，我们将对来自ROR1缺失小鼠的皮肤进行组织学和生化分析，以更确切地确定ROR1在表皮增殖和分化控制中的作用。这些研究将随后进行ROR1和Notch信号通路之间相互调节的机制表征。这项研究的结果将为皮肤生物学提供基本的见解，并可能对开发各种皮肤疾病的新疗法有直接的影响。

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.