The role of microRNA miR-31 in skin biology

描述(申请人提供)：皮肤科领域充满了许多问题，期望从现代生物医学中找到解决方案。几种生物制剂/生物治疗方法，如抗肿瘤坏死因子α抗体，已经在皮肤病患者的日常治疗中产生了影响。然而，前方仍有许多挑战。在我们对皮肤的生物过程的理解上，我们仍然需要填补许多空白。例如，直到最近，一整类小的调节性RNA分子，microRNAs，一直没有被检测到。它们作为几乎所有组织和信号通路中的重要参与者的出现，引导我们探索它们对皮肤生物学的意义。在我们的提案中，我们将重点关注一种microRNA，miR-31，它在许多皮肤病中具有特殊的表达模式。这一发现促使我们研究miR-31在表皮动态平衡、异常生长控制、伤口愈合、应激反应和毛发生长中的功能意义。它参与了主要的皮肤信号通路，如TNFa、TGFb和BMP信号的调节，使其成为控制上皮-间充质转化的中心节点。我们已经确定miR-31在毛囊发生、毛发生长、指甲生长以及对创伤和佛波酯TPA的反应中起着至关重要的作用。TNFa、EGF、Fgf7可诱导miR-31的表达，TGFb可刺激miR-31前体的表达。基于我们现有的miR-31过表达的小鼠模型和我们的初步数据，我们制定了一项研究计划，旨在建立miR-31作为角质形成细胞中EMT、增殖和运动等过程的重要调节因子。因此，我们将能够判断miR-31作为治疗这些过程中存在缺陷的皮肤病的靶点的潜力。我们计划使用我们现有的小鼠模型，并在这项提案中建立新的工具，以应用于我们职业生涯的长期目标，即使用miR-31抑制剂在体内将这些知识转化为miR-31的治疗潜力。在当前研究计划的具体目标1中，我们将测试我们的假设，即miR-31是毛发生长和皮肤对创伤等挑战的反应的关键调节因子。在具体目标2中，我们将解决识别miR-31靶基因的重要问题，以了解miR-31介导的过程。在特定的目标3中，我们将检验我们的假设，即miR-31调控上皮-间充质相互作用和转变，EMI和EMT。此外，我们将测试miR-31是否缓冲了某些表达模式和信号通路，以抵御不必要的波动，并确定除了EMT和毛发生长调节信号网络外，哪些通路确切地受到miR-31的影响。 与公共卫生相关：新的治疗方法的发展受到小RNA分子的发现的推动，这些小分子可以调节基因表达和许多重要的生物学过程，包括所有主要的皮肤病。由于其大小和作用机制，这些被称为microRNAs的小RNA分子是强大的治疗靶点和工具。我们已经确定microRNA miR-31是治疗干预的潜在首选候选基因，因为它的表达模式，对皮肤事件的影响，如毛发生长，它与皮肤癌发生，皮肤老化，以及许多炎症性疾病中的异常生长。

DESCRIPTION (provided by applicant): The field of dermatology is riddled with many problems that expect solutions from modern biomedicine. Several biologicals/biotherapeutical approaches such as anti-TNFalpha antibodies have already made their impact in the daily treatment of dermatology patients. However, many challenges are still ahead. We still have to fill many gaps in our understanding of biological processes in the skin. For example until recently, an entire class of small regulatory RNA molecules, microRNAs, had remained undetected. Their emergence as important players in virtually all tissues and signaling pathways has led us to explore their significance for skin biology. In our proposal we will focus on one microRNA, miR-31, with an exceptional expression pattern in many skin diseases. This finding prompted us to address the functional significance of miR-31 in epidermal homeostasis, aberrant growth control, wound healing, stress response and hair growth. Its involvement in the regulation of major skin signaling pathways such as TNFa, TGFb and BMP signaling makes it a central node for the control of epithelial-mesenchymal transitions. We have identified a crucial role of miR-31 in hair folliculogenesis, hair growth, nail growth, and the response to wounding and the phorbol ester, TPA. TNFa, EGF and FGF7 can induce miR-31 expression and TGFb stimulates the expression of miR-31 precursors. Based on our existing mouse model of miR-31 overexpression and our preliminary data, we have developed a research plan aimed to establish miR-31 as an important regulator of such processes as EMT, proliferation and motility in keratinocytes. Thereby, we will be able to judge the potential of miR-31 as a therapeutic target for skin diseases with defects in these processes. We plan to use our existing mouse model and establish novel tools in this proposal to apply to our career-long goal to translate this knowledge into therapeutic potential of miR-31 using miR-31 inhibitors in vivo. In Specific Aim 1 of this current research plan, we will test our hypothesis that miR-31 is a key regulator of hair growth and the response of the skin to challenges such as wounding. In Specific Aim 2, we will address the important issue of identifying miR-31 target genes to understand miR-31 mediated processes. And in Specific Aim 3, we will test our hypothesis that miR-31 regulates epithelial-mesenchymal interactions and transitions, EMI and EMT. Furthermore, we will test whether miR-31 buffers certain expression patterns and signaling pathways against unwanted fluctuations and define which pathways exactly are influenced by miR-31 in addition to EMT and hair growth regulating signaling networks. PUBLIC HEALTH RELEVANCE: The development of new therapeutic approaches has been invigorated by the discovery of small RNA molecules that can regulate gene expression and many important biological processes including all the major dermatological diseases. These small RNA molecules, called microRNAs, are formidable therapeutic targets and tools due to their size and mechanism of action. We have identified the microRNA miR-31 as potential prime candidate for therapeutic interventions due to its expression pattern, impact on events in the skin such as hair growth, its association with skin carcinogenesis, skin aging, and aberrant growth in many inflammatory disorders.