Defining the role of Toll-like receptor 3 in skin homeostasis, injury and neoplasia

 描述(由申请者提供)：这项建议是一项有指导的培训资助，将研究努力与教学计划相结合，旨在提供免疫学、皮肤生理学/癌症发生方面的强大背景，以及为PI作为独立调查者未来的成功所必需的团队科学方法。长期以来，皮肤病的炎症和免疫相关分子机制一直是PI的研究热点，本研究的重点是研究Toll样受体3在皮肤动态平衡、损伤和肿瘤形成中的作用。TLR3在非黑色素瘤皮肤癌(NMSC)中过表达，目前还没有研究表明TLR3信号通路的激活是否起到保护作用或参与肿瘤的发生和发展。这项建议将使用体外和体内方法来测试TLR3信号通路激活诱导受损角质形成细胞获得类似癌症干细胞的特性，从而促进肿瘤发生的总体假设。在目标1中，我们将检验这样一个假设，即TLR3信号促进角质形成细胞的变化与上皮向间充质转化(EMT)一致。在目标2中，我们将使用体外和体内模型来验证TLR3信号在UVB形成NMSC中起因果作用的假设。这项建议挑战了目前专注于TLR3促炎作用的研究，并强调了它可能作为肿瘤发生的启动者的功能。我们的建议意义重大，因为它将通过增加我们对天然免疫和皮肤肿瘤发生之间的联系的理解，促进皮肤生物学领域的发展。

 DESCRIPTION (provided by applicant): This proposal is a mentored training grant that combines research efforts with a didactic plan designed to provide a strong background in immunology, skin physiology/carcinogenesis and the team science approach necessary for the PI's future success as an independent investigator. The PI has a long-standing interest in the inflammatory and immune-related molecular mechanisms of skin disease and the research focus of this proposal investigates the role of Toll-Like Receptor 3 in skin homeostasis, injury and neoplasia. TLR3 is over- expressed within non-melanoma skin cancers (NMSC) and no study to date has examined whether activation of the TLR3 signaling pathway plays a role in protection or is involved in neoplasia initiation and progression. This proposal will use both in vitro and in vivo methodologies to test the overall hypothesis activation of the TLR3 signaling pathway induces injured keratinocytes to acquire "cancer stem cell-like" properties, which subsequently promotes tumorigenesis. In Aim 1, we will test the hypothesis that TLR3 signaling promotes changes in keratinocytes consistent with an epithelial-to-mesenchymal transition (EMT). In Aim 2, we will use both in vitro and in vivo models to test the hypothesis that TLR3 signaling plays a causal role in formation NMSC by UVB. This proposal challenges current research which focuses on pro-inflammatory role of TLR3 and highlights its likely function as an initiator of tumorigenesis. Our proposal is significant in that it will advance the field of skin biology by increasing our understanding of a link between innate immunity and skin tumorigenesis.