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Basal Cell Polarity Proteins in Normal Tissue Homeostasis and Cancer

正常组织稳态和癌症中的基底细胞极性蛋白

基本信息

批准号：
10667590
负责人：
VALERI VASIOUKHIN
金额：
$ 39.45万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-07 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10667590
关键词：
Address Adult Alleles Animals Apical Applications Grants Basal Cell Biochemical Biological Assay Birth Bromodeoxyuridine Cancer cell line Cell Cycle Cell Death Cell Differentiation process Cell Polarity Cell Separation Cell division Cells Characteristics Chromosomes Complex Data Daughter Development Drosophila genus Ensure Epidermis Event Failure Future Gene Family Gene Targeting Genes Genetic Genetic Crossing Over Grant Heterozygote Homeostasis Knockout Mice Knowledge Laboratories Larva Lesion Lethal Genes Malignant - descriptor Malignant Neoplasms Mammalian Cell Microinjections Mitosis Mitotic spindle Modeling Molecular Mus Mutant Strains Mice Mutation NF-kappa B Normal tissue morphology Organism Orthologous Gene Pathway interactions Patients Phenotype Play Primary Cell Cultures Process Production Proliferating Proteins Regulation Role Signal Transduction Skin Sorting Squamous cell carcinoma Techniques Time Tissues Tumor Suppression Tumor Suppressor Proteins Withdrawal adult stem cell cancer initiation cancer stem cell daughter cell epidermal stem cell experimental study genetic analysis in utero in vivo interest lentivirally transduced mammalian genome model organism mutant neoplastic novel programs self-renewal skin squamous cell carcinoma stem stem cell division stem cell niche stem cell self renewal stem cells stem-like cell targeted treatment tissue culture tumor

项目摘要

Normal tissue homeostasis is maintained by adult stem and progenitor cells that use cell intrinsic mechanisms and information from their microenvironment to execute a very complex specialized type of mitosis known as asymmetric cell division. Two resulting from this division daughter cells acquire different cell fates. While one cell continues proliferation, another daughter cell withdraws from the stem cell niche, remodels its intercellular interactions and starts a program which ultimately leads to the cell cycle withdrawal and differentiation. This process ensures that only the necessary number of cells is produced at any given time and the cell death and depletion in each tissue is balanced by the birth of new cells. Defective asymmetric cell division can result in the failure of normal tissue homeostasis and birth of cancer stem cells, which cannot produce daughters that can properly withdraw from the cell cycle and differentiate. While asymmetric cell division plays a pivotal role in tissue homeostasis, little is known about its mechanisms in mammalian organisms. Studies in model organisms revealed critical role of intercellular interactions and apical-basal cell polarity in regulation of asymmetric cell division. In Drosophila, basal cell polarity gene lethal giant larvae (lgl) was identified as an important regulator of asymmetric cell division, and mutations in lgl result in overproduction of dividing stem cells and development of cancer. Mammalian genomes contain two lgl orthologs Llgl1 and Llgl2. While previous studies of LLGL1 and LLGL2 in cancer cell lines indicated their potential role as tumor suppressors, genetic analysis of these genes in mice was complicated by the genetic redundancy and lethality of Llgl mutants. We have now generated conditional, tissue specific Llgl1/2 double knockout mice. Our preliminary experiments revealed tumor-suppressive function of Llgl1/2 in skin squamous cell carcinoma. In this grant, we propose to use our mutant animals, primary cell cultures and in utero lentiviral transduction of skin epidermis to reveal the role and molecular mechanisms of Llgl gene family in stem and progenitor cells during normal tissue homeostasis and cancer. These studies will help to understand the mechanisms of mammalian stem and progenitor cells self-renewal and differentiation and the role of these mechanisms in cancer.

正常的组织稳态由成体干细胞和祖细胞维持，机制和信息来执行非常复杂的专用类型有丝分裂称为不对称细胞分裂。由此产生的两个子细胞获得不同的细胞命运当一个细胞继续增殖时，另一个子细胞从干细胞中退出细胞龛，重塑其细胞间的相互作用，并启动一个程序，最终导致细胞周期退出和分化。这个过程确保了只有必要数量的细胞被在任何给定的时间产生，每个组织中的细胞死亡和消耗都由新的细胞有缺陷的不对称细胞分裂可导致正常组织稳态的失败，癌症干细胞的诞生，它不能产生可以正确退出细胞的子细胞循环和分化。虽然不对称细胞分裂在组织稳态中发挥着关键作用，但很少已知其在哺乳动物中的作用机制。对模式生物的研究表明，细胞间相互作用和顶基细胞极性在调节细胞不对称分裂中的作用。在果蝇中，基底细胞极性基因致死性巨幼虫（lgl）被确定为一个重要的调节因子不对称的细胞分裂，lgl的突变导致分裂干细胞的过度产生，癌症的发展。哺乳动物基因组含有两个lgl直系同源物Llgll和Llgl2。虽然以前的 LLGL 1和LLGL 2在癌细胞系中的研究表明它们作为肿瘤抑制剂的潜在作用，小鼠中这些基因的遗传分析由于Llgl的遗传冗余和致死性而变得复杂变种人我们现在已经产生了条件性的、组织特异性的Llgl1/2双敲除小鼠。我们初步实验显示Llgl 1/2在皮肤鳞状细胞中具有抑瘤功能， carcinoma.在这项资助中，我们建议使用我们的突变动物，原代细胞培养和子宫内慢病毒转导皮肤表皮揭示Llgl基因家族的作用和分子机制在正常组织稳态和癌症期间的干细胞和祖细胞中。这些研究将有助于了解哺乳动物干细胞和祖细胞自我更新和分化的机制以及这些机制在癌症中的作用。