Differentiation balances oncogene-driven proliferation to maintain epidermal homeostasis

项目摘要 在皮肤上皮中，祖细胞群体明显能够增殖，自我更新， 终末分化为有丝分裂后后代，负责维持整个生命期的组织稳态。 与增殖和凋亡不同，目前使用定性或间接测定来评估细胞命运选择。 因此，我们缺乏对祖细胞在皮肤生长过程中如何平衡增殖与分化的充分理解。 发育和体内平衡，或皮肤的生长障碍。 我们的长期目标是确定表皮祖细胞如何平衡生长， 致癌基因突变来维持组织内环境稳定。为此，我们开发了一种新的检测方法， 稳态和过度增殖过程中表皮祖细胞自我更新和分化的速率 增长我们将在小鼠模型中使用我们的测定，这些小鼠模型被工程化以表达生理水平的 在皮肤中具有组成性活性的Hras和Pik 3ca。另外，我们将使用我们最近开发的快速基因- 靶向方法，探索RAS-PI 3 K信号转导的特异性效应物和底物如何修饰表皮 体内分化。 本申请旨在测试以下假设：1.）增加分化可以平衡促有丝分裂 致癌信号传导对维持组织稳态的作用; 2.）Ras效应子Pik 3ca启动一种分子 包括Akt和特异性Akt底物的级联反应，以调节祖细胞的更新和分化， 皮肤表皮;和3.）表皮祖细胞对癌基因表达的反应是异质的， 受祖细胞生态位的影响。 我们的研究结果有望立即揭示细胞和分子原理， 维持皮肤的稳态和功能，尽管有大量的生长促进突变。这些 这一发现将是开发操纵祖细胞的药理学策略的关键一步。 在表皮中的潜力，以治疗以不受限制的组织生长为标志的病症。

Project Summary In skin epithelium, a population of progenitor cells distinctly capable of proliferation, self-renewal, and terminal differentiation into post-mitotic progeny, is responsible to sustain tissue homeostasis throughout life. Unlike proliferation and apoptosis, cell fate choices are currently assessed using qualitative or indirect assays. As a result, we lack full understanding of how progenitors balance proliferation with differentiation during skin development and homeostasis, or in growth disorders of the skin. Our long-term objective is to establish how epidermal progenitor cells balance growth in the presence of oncogenic mutations to maintain tissue homeostasis. To do so, we developed a novel assay to directly quantify rates of progenitor cell self-renewal and differentiation in epidermis during homeostatic and hyperproliferative growth. We will employ our assay in the mouse models engineered to express physiological levels of constitutively active Hras and Pik3ca in the skin. In addition, we will use our recently developed rapid gene- targeting method, to explore how specific effectors and substrates of RAS-PI3K signaling modify epidermal differentiation in vivo. This application aims to test the hypotheses that: 1.) Increased differentiation can balance mitogenic effects of oncogenic signaling to maintain tissue homeostasis; 2.) Ras effector Pik3ca initiates a molecular cascade that includes Akt and specific Akt substrates to regulate progenitor cell renewal and differentiation in skin epidermis; and 3.) Epidermal progenitor response to oncogene expression is heterogeneous and influenced by progenitor cell niche. The results of our research are expected to immediately uncover cellular and molecular principles that maintain skin homeostasis and functionality despite the abundance of growth-promoting mutations. These findings will be a critical step in development of pharmacological strategies to manipulate progenitor cell potential in the epidermis, to treat conditions marked by unrestrained tissue growth.