Function of Sprouty Genes in Skin Stem Cells and Skin Carcinogenesis

描述（由申请人提供）：受体酪氨酸激酶（RTK）信号通路对许多不同类型癌症的发生和发展至关重要。发芽基因是已知的RTK信号通路的负反馈调节因子。已经鉴定出4个芽生基因，其中3个在大多数组织中主要表达（如Sprouty1， Sprouty2, Sprouty4）。发芽基因产物发挥作用的确切机制尚不清楚。然而，有大量已发表的文献将低Sprouty基因表达与人类癌症联系起来，表明Sprouty基因可能起到肿瘤抑制因子（抑制肿瘤生长的基因）的作用。这些研究大多基于关联研究，因此很难确切地知道减少的Sprouty表达是发生在肿瘤形成之前还是之后。此外，许多研究集中于删除一个，有时两个，斯普劳迪基因，以评估其作为肿瘤抑制因子的功能。由于尚不清楚当一个斯普罗蒂基因的表达被沉默时，斯普罗蒂基因是否能够相互补偿，我们可能还没有充分认识到这个基因家族在防止肿瘤形成方面的全部影响。一项系统遗传学研究表明，小鼠皮肤中Sprouty2表达水平的提高对皮肤肿瘤的形成具有保护作用。为了探索史普罗蒂基因在预防皮肤癌中可能发挥的作用，我将使用缺乏三种最主要表达史普罗蒂基因基因表达的转基因小鼠。这些小鼠将接受致癌物治疗，这些致癌物会导致皮肤肿瘤的形成。如果斯普罗蒂基因是皮肤中的肿瘤抑制因子，我预计，与正常小鼠相比，缺失这三种斯普罗蒂基因的小鼠会形成更多的肿瘤。这个基因小鼠皮肤癌模型将使我能够直接测试斯普罗蒂基因是否能预防皮肤癌症。此外，为了探索灭活Sprouty基因在细胞水平上的影响，我将分离缺乏Sprouty基因的小鼠皮肤干细胞，并对其进行一些生化实验。了解史普罗蒂基因的潜在生物学效应将增加我们对皮肤和癌症生物学的认识，并可能为未来皮肤癌的治疗靶点提供线索。

DESCRIPTION (provided by applicant): Receptor tyrosine kinase (RTK) signaling pathways are crucial to the initiation and progression of many different types of cancer. Sprouty genes are known negative feedback regulators of RTK signaling pathways. Four Sprouty genes have been identified, three of which are predominantly expressed in most tissues (e.g. Sprouty1, Sprouty2, Sprouty4). The exact mechanism by which Sprouty gene products function is not wel understood. However, there is a significant amount of published literature that links low Sprouty gene expression with human cancers, suggesting that Sprouty genes may act as tumor suppressors (genes that suppress tumor growth). Most of this research is based on association studies, making it difficult to know with certainty whether decreased Sprouty expression occurs before or after tumors form. Additionally, many of these studies focused on deleting one, sometimes two, Sprouty genes to assess their function as tumor suppressors. Since it is not clear if Sprouty genes are able to compensate for one another when expression of one Sprouty gene is silenced, we may not yet appreciate the full impact that this family of genes has on preventing tumors from forming. A systems genetics study has shown that increased levels of Sprouty2 expression in mouse skin are protective against the formation of skin tumors24. In order to explore the role that Sprouty genes may play in preventing skin cancer, I will use genetically modified mice that lack gene expression from the three most predominantly expressed Sprouty genes. These mice will be treated with carcinogens that cause skin tumors to form. If Sprouty genes are tumor suppressors in the skin, I expect to see more tumors form in mice that are missing the three Sprouty genes compared to normal mice. This genetic mouse skin cancer model will allow me to directly test if Sprouty genes prevent cancer in the skin. Additionally, in order to explore the effects of inactivating Sprouty genes at the cellular level, I will isolate mouse skin stem cells that lack Sprouty genes and perform several biochemical experiments on them. Understanding the underlying biological effects of Sprouty genes will increase our knowledge of both skin and cancer biology, and could provide clues about future therapeutic targets for skin cancer.