Hippo signaling and the control of epidermal development and growth

描述(申请人提供)：成人组织干细胞被认为负责维持身体组织损伤后的组织动态平衡和再生。因此，对组织特异性干细胞的生物学和控制其行为的信号通路的基本了解对于它们在疾病治疗中的潜在应用至关重要。这个 果蝇河马途径通过调节转录激活因子York kie来调节器官大小。我们最近证明了河马信号在哺乳动物组织中是活跃的，它也可以调节器官的大小。特别是在皮肤中，河马途径的转录效应因子YAP1对于发育过程中适当的表皮组织扩张是必不可少的。YAP1的过度激活会导致祖细胞的扩张和肿瘤的发展。这里的具体假设是，河马途径作用于干细胞室，并在组织生长和肿瘤形成期间需要时扩大未分化的祖细胞。在这项建议中，我们的目标是获得新的机制洞察河马信号在皮肤生物学中的作用。我们的计划利用了我们实验室创造的独特的基因工具。在目标1中，我们建议利用河马信号传感器来表征皮肤中具有最高水平YAP活性的细胞。此外，我们将充分描述由于YAP及其同系物TAZ在皮肤中的缺失而导致的发育异常。在目标2中，我们将使用全基因组结合分析在原代表皮祖细胞中识别和表征YAP活性的关键介质。最后，在目标3中，我们将探索河马和Hedgehog信号在表皮基底细胞癌生长过程中之前被低估的关系。我们的研究有助于更好地了解表皮干细胞生物学，并为这些关键细胞的扩增、鉴定和治疗目的提供新的模型和策略。 与公共卫生相关：正常组织在达到正确大小时遇到的障碍可能会影响肿瘤发生的非常早期阶段。在这里，我们建议阐明调节哺乳动物器官大小的途径是如何控制干细胞的，干细胞被认为是肿瘤发生的关键角色，并且在癌症中被解除调控。更全面地了解这一通路的活性在发育过程中如何被控制，以及在肿瘤发生过程中如何被解除调控，可能会为未来的癌症治疗提供合适的靶点。

DESCRIPTION (provided by applicant): Adult tissue stem cells are thought to be responsible for maintaining tissue homeostasis and regeneration following injury in somatic tissues. Thus, basic understating of the biology of tissue-specific stem cells and the signaling pathways the control their behavior is critical for their potential application in the treatment of disease. The Drosophila Hippo pathway regulates organ size through regulation of the transcriptional activator Yorkie. We have recently demonstrated that Hippo signaling is active in mammalian tissues and that it can also regulate organ size. Particularly, in the skin, the transcriptional effector of the Hippo pathway, YAP1, is essential for proper epidermal tissue expansion during development. Over-activation of YAP1 leads to progenitor expansion and tumor development. The specific hypothesis here is that the Hippo pathway acts on stem cell compartments and expands undifferentiated progenitor cells when needed during tissue growth, and during tumorigenesis. In this proposal, we aim to gain novel mechanistic insight into the role of Hippo signaling in skin biology. Our proposal makes use of unique genetic tools that our laboratory has generated. In Aim 1, we propose to utilize a Hippo-signaling sensor to characterize the cells in the skin that have highest levels Yap activity. Additionally, we will fully characterize the developmental abnormalities caused by the loss of YAP and its homologue TAZ in the skin. In Aim 2, we will identify and characterize the critical mediators of YAP activity using genome-wide binding analysis in primary epidermal progenitors. Finally in Aim 3, we will explore a previously under-appreciated relationship between Hippo and Hedgehog signaling during epidermal basal cell carcinoma growth. Our studies could lead to a better understanding of epidermal stem cell biology, and new models and strategies for expansion, characterization and manipulation of these critical cells for therapeutic purposes. PUBLIC HEALTH RELEVANCE: The barrier that normal tissues encounter when they have reached the correct size is likely to impact on the very early stages of tumorigenesis. Here we propose to elucidate how a pathway that regulates organ size in mammals controls stem cells, which are thought to be key players in tumorigenesis, and is deregulated in cancer. A more complete understanding of how activity of this pathway is controlled during development and deregulated during tumorigenesis may highlight suitable targets for future cancer therapeutics.