Differentiation balances oncogene-driven proliferation to maintain epidermal homeostasis

分化平衡癌基因驱动的增殖以维持表皮稳态

基本信息

批准号：
10210188
负责人：
Slobodan Beronja
金额：
$ 22.48万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-27 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10210188
关键词：
Adult Apoptosis Automobile Driving Biochemistry Biological Assay Cell Cycle Cell division Cells Cessation of life DNA Damage Data Development Disease Engineering Ensure Environmental Hazards Epidermis Epithelial Equilibrium Exposure to Gene Targeting Genes Genetic Epistasis Genetic Screening Goals Growth Growth Disorders Hair follicle structure Homeostasis Human Hyperplasia Image Knowledge Label Life Maintenance Malignant Neoplasms Mediating Methods Mitotic Molecular Mus Mutation Oncogenes Oncogenic Outcome Pathologic Pathway interactions Pharmacology Phosphorylation Physiologic pulse Physiological Population Process Proliferating Publishing Reporter Research Signal Transduction Skin Testing Time Tissue Expansion Tissues Wild Type Mouse base combat daughter cell epidermal stem cell epithelial stem cell experimental study genetic testing improved in vivo intravital imaging loss of function man mouse model novel novel therapeutic intervention progenitor response self-renewal skin disorder skin organogenesis stem cell proliferation stem cells targeted treatment therapy design two-photon

项目摘要

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.

项目摘要在皮肤上皮中，祖细胞群明显能够增殖，自我更新和末端分化为有丝分裂后的后代，负责在一生中维持组织稳态。与增殖和凋亡不同，目前使用定性或间接测定法评估细胞命运选择。结果，我们对祖细胞如何在皮肤期间如何平衡扩散与分化不完全了解发育和稳态，或皮肤生长障碍。我们的长期目标是确定表皮祖细胞在存在下如何平衡生长致癌突变以维持组织稳态。为此，我们开发了一种新颖的测定法以直接量化稳态和增强性超增长期间表皮的祖细胞自我更新和分化的速率生长。我们将在设计的鼠标模型中使用我们的测定法，以表达生理水平皮肤中的组成性活跃的HRA和PIK3CA。此外，我们将使用我们最近开发的快速基因靶向方法，探索RAS-PI3K信号传导的特定效应子和底物如何修饰表皮体内分化。该应用程序旨在测试以下假设：1。）增加的分化可以平衡有丝分裂致命信号传导维持组织稳态的影响； 2.）RAS效应器PIK3CA启动分子包括AKT和特定AKT底物的级联，以调节祖细胞更新和分化皮肤表皮； 3.）表皮祖细胞对癌基因表达的反应是异质的，受祖细胞小众的影响。我们的研究结果有望立即发现细胞和分子原理尽管有丰富的增长突变，但仍保持皮肤稳态和功能。这些调查结果将是制定操纵祖细胞的药理策略的关键步骤在表皮中的潜力，以治疗以不受约束的组织生长为标志的条件。