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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：
9384220
负责人：
Slobodan Beronja
金额：
$ 38.72万
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9384220
关键词：
Adult Alpha Cell 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 Epithelium Equilibrium Exposure to Gene Targeting Genes Genetic Epistasis Genetic Screening Genetic screening method 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 Stem cells Testing Time Tissue Expansion Tissues Wild Type Mouse base combat daughter cell experimental study improved in vivo intravital imaging loss of function man mouse model novel novel therapeutics progenitor response self-renewal skin disorder skin organogenesis 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.

项目总结