The role of microRNA miR-31 in skin biology

描述（申请人提供）：皮肤病学领域充斥着许多问题，需要现代生物医学来解决。一些生物制剂/生物治疗方法，如抗tnfalpha抗体，已经在皮肤病患者的日常治疗中发挥了作用。然而，前方仍有许多挑战。我们仍然需要填补我们对皮肤生物过程理解的许多空白。例如，直到最近，一整类小调控RNA分子，即microrna，仍未被发现。它们在几乎所有组织和信号通路中扮演着重要角色，这促使我们探索它们对皮肤生物学的意义。在我们的建议中，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在表皮稳态、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。它参与调节主要的皮肤信号通路，如TNFa、TGFb和BMP信号通路，使其成为控制上皮-间质转化的中心节点。我们已经确定了miR-31在毛囊发生、头发生长、指甲生长以及对损伤和酚酯TPA的反应中的关键作用。TNFa、EGF和FGF7可诱导miR-31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作为角化细胞中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作为在这些过程中存在缺陷的皮肤病的治疗靶点的潜力。我们计划使用我们现有的小鼠模型，并在本提案中建立新的工具，以应用于我们的职业长期目标，将这些知识转化为体内使用miR-31抑制剂的miR-31的治疗潜力。在本研究计划的Specific Aim 1中，我们将验证我们的假设，即miR-31是头发生长和皮肤对损伤等挑战反应的关键调节因子。在Specific Aim 2中，我们将解决鉴定miR-31靶基因以了解miR-31介导过程的重要问题。在特异性目标3中，我们将验证我们的假设，即miR-31调节上皮-间质相互作用和转变，EMI和EMT。此外，我们将测试miR-31是否缓冲某些表达模式和信号通路免受不必要的波动，并确定除了EMT和毛发生长调节信号网络外，哪些途径确切地受到miR-31的影响。

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.