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

 描述（由申请人提供）：该提案是一项指导性培训补助金，将研究工作与教学计划相结合，旨在提供免疫学、皮肤生理学/致癌作用方面的强大背景，以及PI未来作为独立研究者取得成功所需的团队科学方法。PI长期以来一直对皮肤病的炎症和免疫相关分子机制感兴趣，本提案的研究重点是研究Toll样受体3在皮肤稳态，损伤和肿瘤形成中的作用。TLR 3在非黑素瘤皮肤癌（NMSC）中过表达，并且迄今为止没有研究检查TLR 3信号传导途径的激活是否在保护中起作用或参与瘤形成的起始和进展。该提案将使用体外和体内方法来测试TLR 3信号传导途径的激活诱导受损角质形成细胞获得“癌症干细胞样”性质的总体假设，其随后促进肿瘤发生。在目标1中，我们将检验TLR 3信号传导促进角质形成细胞中与上皮向间充质转化（EMT）一致的变化的假设。在目标2中，我们将使用体外和体内模型来测试TLR 3信号传导在UVB形成NMSC中起因果作用的假设。这一提议挑战了目前专注于TLR 3促炎作用的研究，并强调了其作为肿瘤发生引发剂的可能功能。我们的建议是重要的，因为它将通过增加我们对先天免疫和皮肤肿瘤发生之间联系的理解来推进皮肤生物学领域。

 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.