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:
  • 金额:
    $ 39.45万
  • 依托单位:
  • 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

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.
正常组织的稳态由成体干细胞和祖细胞维持,它们利用细胞内在的 来自微环境的机制和信息来执行非常复杂的专门类型 有丝分裂称为不对称细胞分裂。该分裂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 细胞生态位,重塑其细胞间相互作用并启动一个程序,最终导致细胞 循环退出和分化。这个过程确保只有必要数量的细胞 在任何给定时间产生,并且每个组织中的细胞死亡和消耗通过产生来平衡 新细胞。有缺陷的不对称细胞分裂可能导致正常组织稳态失败 癌症干细胞的诞生,无法产生能够正常退出细胞的子细胞 循环并微分。虽然不对称细胞分裂在组织稳态中发挥着关键作用,但很少有 已知其在哺乳动物有机体中的机制。对模式生物的研究揭示了关键 细胞间相互作用和顶基底细胞极性在不对称细胞分裂调节中的作用。 在果蝇中,基底细胞极性基因致死巨幼虫(lgl)被确定为重要的调节因子 不对称细胞分裂和lgl突变导致分裂干细胞的过度产生 癌症的发展。哺乳动物基因组包含两个lgl直系同源物Llgl1和Llgl2。虽然之前 对癌细胞系中 LLGL1 和 LLGL2 的研究表明它们作为肿瘤抑制因子的潜在作用, 由于 Llgl 的遗传冗余和致死性,对小鼠中这些基因的遗传分析变得复杂 突变体。我们现在已经产生了有条件的、组织特异性的 Llgl1/2 双敲除小鼠。我们的 初步实验揭示Llgl1/2在皮肤鳞状细胞中的抑癌功能 癌。在这笔赠款中,我们建议使用我们的突变动物、原代细胞培养物和子宫内 皮肤表皮慢病毒转导揭示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。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
YAP1 and its fusion proteins in cancer initiation, progression and therapeutic resistance.
  • DOI:
    10.1016/j.ydbio.2020.12.018
  • 发表时间:
    2021-07
  • 期刊:
  • 影响因子:
    2.7
  • 作者:
    Szulzewsky F;Holland EC;Vasioukhin V
  • 通讯作者:
    Vasioukhin V
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VALERI VASIOUKHIN其他文献

VALERI VASIOUKHIN的其他文献

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{{ truncateString('VALERI VASIOUKHIN', 18)}}的其他基金

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
  • 批准号:
    10406262
  • 财政年份:
    2019
  • 资助金额:
    $ 39.45万
  • 项目类别:
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
  • 批准号:
    9814413
  • 财政年份:
    2019
  • 资助金额:
    $ 39.45万
  • 项目类别:
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
  • 批准号:
    10601295
  • 财政年份:
    2019
  • 资助金额:
    $ 39.45万
  • 项目类别:
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
  • 批准号:
    10158454
  • 财政年份:
    2019
  • 资助金额:
    $ 39.45万
  • 项目类别:
Alpha-Catenin in Regulation of Tissue Homeostasis and Cancer
α-连环蛋白调节组织稳态和癌症
  • 批准号:
    8643463
  • 财政年份:
    2014
  • 资助金额:
    $ 39.45万
  • 项目类别:
Alpha-Catenin in Regulation of Tissue Homeostasis and Cancer
α-连环蛋白调节组织稳态和癌症
  • 批准号:
    9057992
  • 财政年份:
    2014
  • 资助金额:
    $ 39.45万
  • 项目类别:
Regulation of Hippo Signaling by Src-Family Kinases
Src 家族激酶对 Hippo 信号传导的调节
  • 批准号:
    8764489
  • 财政年份:
    2014
  • 资助金额:
    $ 39.45万
  • 项目类别:
The Hippo Pathway in Prostate Gland Homeostasis and Prostate Cancer
前列腺稳态和前列腺癌中的 Hippo 通路
  • 批准号:
    9228337
  • 财政年份:
    2013
  • 资助金额:
    $ 39.45万
  • 项目类别:
The Hippo Pathway in Prostate Gland Homeostasis and Prostate Cancer
前列腺稳态和前列腺癌中的 Hippo 通路
  • 批准号:
    8517420
  • 财政年份:
    2013
  • 资助金额:
    $ 39.45万
  • 项目类别:
The Hippo Pathway in Prostate Gland Homeostasis and Prostate Cancer
前列腺稳态和前列腺癌中的 Hippo 通路
  • 批准号:
    9005838
  • 财政年份:
    2013
  • 资助金额:
    $ 39.45万
  • 项目类别:

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