Regulation of hair follicle development by the miR-200 family

描述（由申请人提供）：适当的皮肤和头发发育对人类健康和情感幸福至关重要。彻底了解这些过程和控制它们的机制将有助于开发许多疾病的治疗方法。在毛发形态发生过程中，表皮祖细胞将来自底层真皮乳头（DP）的分子“指令”与细胞自主信号相结合，导致毛囊（HFs）的重新形成。尽管做了大量的努力，但我们对导致心衰发展的上皮-间充质相互作用的理解仍然不完整。最近，microrna参与了许多重要的发育过程，包括皮肤和HF的形态发生。miR-200家族已被证明在上皮性癌症中调节上皮-间充质转化（EMT），初步原位杂交数据显示它们在HF的前沿上调，使其成为调节HF形态发生的有希望的候选物。该项目的第一个目标是确定miR-200s在调节角质形成细胞迁移和增殖中的细胞自主作用，这将通过操纵培养的角质形成细胞中的miR-200s水平来实现。本研究的第二个目的是确定miR-200s在HF形态发生过程中调节上皮-间质相互作用中的作用。利用在表皮和毛囊中特异性过表达miR-200s的转基因小鼠，通过形态学分析来检测miR-200s过表达对HF形态发生的影响。本研究的第三个也是最后一个目的是确定HF前沿miR-200家族成员的体内靶点。FACS纯化将与完善的miRNA靶点鉴定管道相结合，以鉴定HF前沿的miR-200s特异性靶点。体外和体内研究的结合将有助于了解miR- 200s在HF形态发生中的作用。此外，确定miR-200s的靶点对于阐明其功能至关重要。更全面地了解miR-200家族在小鼠皮肤和HF中的功能将有助于我们对皮肤和HF发展的总体理解，这将对开发许多疾病的治疗方法至关重要。

DESCRIPTION (provided by applicant): Proper skin and hair development are crucial for human health and emotional well-being. Having a thorough understanding of these processes and the mechanisms that govern them will aid in developing treatments for many diseases. During hair morphogenesis, epidermal progenitors integrate molecular 'instructions' emanating from the underlying dermal papillae (DP) with cell-autonomous signals, leading to de novo formation of hair follicles (HFs). Despite extensive efforts, our understanding of the epithelial- mesenchymal interactions that lead to HF development remain incomplete. Recently, microRNAs have been implicated in many important processes in development, including skin and HF morphogenesis. The miR-200 family has been shown to regulate epithelial-to-mesenchymal transition (EMT) in epithelial cancers, and preliminary in situ hybridization data shows that they are up-regulated at the leading edge of HFs, making them a promising candidate for regulating HF morphogenesis. The first aim of this project entails determining the cell-autonomous role of miR-200s in the regulation of migration and proliferation of keratinocytes, which will be accomplished through the manipulation of miR-200s' levels in cultured keratinocytes. The second aim of the proposed research involves determining the role of miR-200s in regulating epithelial-mesenchymal interactions during HF morphogenesis. Using a transgenic mouse over-expressing miR-200s specifically in the epidermis and hair follicle, the effects of miR-200s over-expression on HF morphogenesis will be examined through morphological analysis. The third and final aim of this research is to identify in vivo targets of miR-200 family members in the leading edge of the HF. FACS purification will be combined with a well-established miRNA target identification pipeline to identify miR-200s' specific targets in the leading edge of the HF. The combination of in vitro and in vivo studies proposed will contribute greatly to understanding the role of miR- 200s during HF morphogenesis. In addition, identifying targets of miR-200s will be crucial for elucidating their function. A more thorough understanding of miR-200 family function in murine skin and HFs will aid in our general understanding of skin and HF development, which will be crucial for developing therapies for many diseases.