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Mammary basal/stem cell plasticity and regulation

乳腺基底/干细胞可塑性和调节

基本信息

批准号：
9557556
负责人：
Xing Dai
金额：
$ 42.73万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2017-09-10 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9557556
关键词：
Address Adopted Adult Affect Animals Area Back Basal Cell Biological Assay Biological Models Biology Breast Epithelial Cells Cancer Etiology Cell Differentiation process Cell Fate Control Cell Line Cells Characteristics Colony-Forming Units Assay Coupled Data Development Disease Distant Metastasis Embryonic Development Epiblast Epigenetic Process Epithelial Epithelial Cells Equilibrium Failure Fibrosis Genetic Goals Heterogeneity Homeostasis In Vitro Individual Knockout Mice Knowledge Learning Link Literature Maintenance Malignant - descriptor Mammary gland Mesenchymal Mesoderm Methods Modeling Molecular Molecular Target Morphogenesis Multipotent Stem Cells Mus Natural regeneration Organ Pathologic Pathologic Processes Physiological Play Pluripotent Stem Cells Population Population Heterogeneity Positioning Attribute Pregnancy Process Property Puberty Regenerative Medicine Regulation Repression Research Role Self-control as a personality trait Somatic Cell Stem cells Stimulus Stratum Basale Subgroup Technology Testing Tissue Engineering Tissues Transitional Cell Transplantation Work Wound Healing adult stem cell cancer cell cell type design epithelial to mesenchymal transition experimental study fluidity genetic signature in vivo in vivo regeneration inhibitor/antagonist knock-down knockout gene malignant breast neoplasm mammary epithelium mammary gland development mathematical model novel overexpression prevent prospective regenerative self-renewal single cell analysis single-cell RNA sequencing stem stem cell fate stem cell therapy stemness trait transcription factor transcriptomics tumor progression

项目摘要

PROJECT SUMMARY The ability to reprogram myriad differentiated cells back into a pluripotent stem cell state highlights the remarkable plasticity of somatic cells. Effort is needed to better understand the inherent plasticity of tissue stem cells as well as the underlying regulatory mechanisms, so that we can learn about how to control cell fates in tissue engineering and regenerative medicine. Epithelial cells are long known to possess inherent plasticity, best manifested by their ability to become mesenchymal cells as well as to revert back to an epithelial state, under appropriate stimuli. This plasticity is important for generating mesenchymal cell types during embryogenesis, and is thought to be required for malignant cancer cells to form distant metastases. Recent studies have inspired the hypothesis that the mechanisms that regulate this plasticity are used in committed tissue epithelial cells to control stem cell fates. The mammary epithelia serve an outstanding model system to test this hypothesis, owing to the well-established methods to prospectively isolate and functionally characterize their residential stem cells. The basal layer of the mammary epithelia harbors multipotent stem cells and cells that can turn into such stem cells under conditions such as transplantation and pregnancy. We will organically combine cutting-edge single-cell analysis with state-or-art technology such as tissue-specific gene knockout and inducible overexpression, in vivo and ex vivo stem cell assays, as well as molecular studies to address the following fundamentally important questions: 1) How many cell type subsets or cellular states exist in the mammary basal cell population and do these states correspond to distinct positions in the spectrum of epithelial/EMT plasticity? 2) Are multipotent stem cells or cells with the capacity to become such stem cells defined in part by their high plasticity, namely the potential to adopt both mesenchymal-like and terminal epithelial fates? 3) What is the key molecular circuitry that regulates such plasticity, and whether/how this circuitry dictates the stay of a basal cell in a stem cell state?

项目总结