VTCN1 regulation of MHC in early human placental development

VTCN1 对人类早期胎盘发育中 MHC 的调节

基本信息

  • 批准号:
    10092932
  • 负责人:
  • 金额:
    $ 19.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-01-31 至 2022-07-01
  • 项目状态:
    已结题

项目摘要

Improper peri-implantation placental development may contribute to feto-maternal diseases (preterm birth, intrauterine growth retardation, preeclampsia) and high rates of pregnancy loss. Since these events occur prior to clinical detection of pregnancy, studies of very early human placental development are ethically and logistically constrained. The proposed project uses an innovative human embryonic stem cell (hESC)-derived model to study primitive trophoblast in vitro. The placenta resembles a cancer in that an implanting fetus and a developing cancer both involve host tissue invasion, massive cellular proliferation, neo-vascularization, and alterations in the immediate immune microenvironment. The placenta of the implanting fetus is one of the only non-cancerous tissues that displays physiologic downregulation of the classical major histocompatibility complex (MHC) class I (MHC-I) transplantation antigens, human leukocyte antigens (HLA)-A and -B. While positive regulatory elements for MHC class II regulation are described, little is known about such regulation of MHC class I expression in noncancerous tissues, including the placenta. Human embryonic stem cells (hESCs) have been used in a novel in vitro model of the stages of human placental development that occur prior to clinical detection of pregnancy. Several mRNAs and proteins that are selectively expressed at high levels in early pregnancy have been identified by using the model. Of those studied, all appear to play roles in invasion. Remarkably, siRNA silencing of one of these proteins, V-Set Domain Containing T Cell Activation Inhibitor 1 (VTCN1), in our model for early trophoblast strongly up-regulated the expression of the MHC class I human leukocyte antigens (HLA)-A and -B, which are normally not expressed in human trophoblast, slightly up-regulated the normally resident HLA-C, but had no effect on expression of the placenta-specific HLA-G. VTCN1 is recognized as a member of the B7 superfamily of cell-surface co-receptors that regulate T cell receptor interactions with MHC molecules. It has been postulated that VTCN1 neo-expression affects cancer cells’ ability to evade host immune detection. These results highlight the efficacy of our in vitro models for filling several important knowledge gaps. The unique ability to model peri-implantation placental development in vitro will enable dissection of the control of MHC-I expression on human trophoblast (TB), particularly testing the hypothesis that the lack of expression of HLA-A and -B by TB is controlled by VTCN1 through largely indirect mechanisms. There are three aims to the proposal: 1) Demonstrate classical MHC class I suppression by VTCN1 in various TB models, including hESC-derived primitive trophoblast, by using VTCN1 knock-down and overexpression; 2) Define the transcriptional pathways and transcriptional and immediate post-transcriptional regulation involved in VTCN1-related alterations in TB MHC-I expression and 3) Identify protein partners of VTCN1 in in vitro cell models of early TB to discover and confirm pathways involved in VTCN1 regulation of MHC class I expression. These studies will have application to the origins of common disorders of abnormal placentation and to the understanding of cancer immunology.
不适当的植入期胎盘发育可能导致胎母疾病(早产、宫内)

项目成果

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Toshihiko Ezashi其他文献

Toshihiko Ezashi的其他文献

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{{ truncateString('Toshihiko Ezashi', 18)}}的其他基金

VTCN1 regulation of MHC in early human placental development
VTCN1 对人类早期胎盘发育中 MHC 的调节
  • 批准号:
    9892559
  • 财政年份:
    2020
  • 资助金额:
    $ 19.38万
  • 项目类别:
Modeling normal and abnormal trophoblasts
正常和异常滋养层建模
  • 批准号:
    9980204
  • 财政年份:
    2018
  • 资助金额:
    $ 19.38万
  • 项目类别:
Modeling normal and abnormal trophoblasts
正常和异常滋养层建模
  • 批准号:
    10188575
  • 财政年份:
    2018
  • 资助金额:
    $ 19.38万
  • 项目类别:
Modeling normal and abnormal trophoblasts
正常和异常滋养层建模
  • 批准号:
    10427186
  • 财政年份:
    2018
  • 资助金额:
    $ 19.38万
  • 项目类别:
Modeling normal and abnormal trophoblasts
正常和异常滋养层建模
  • 批准号:
    9790972
  • 财政年份:
    2018
  • 资助金额:
    $ 19.38万
  • 项目类别:
Pluripotent Stem Cells: Modeling syncytiotrophoblast development and pathogenesis
多能干细胞:模拟合体滋养层发育和发病机制
  • 批准号:
    8841613
  • 财政年份:
    2013
  • 资助金额:
    $ 19.38万
  • 项目类别:
Pluripotent Stem Cells: Modeling syncytiotrophoblast development and pathogenesis
多能干细胞:模拟合体滋养层发育和发病机制
  • 批准号:
    9084586
  • 财政年份:
    2013
  • 资助金额:
    $ 19.38万
  • 项目类别:
Pluripotent Stem Cells: Modeling syncytiotrophoblast development and pathogenesis
多能干细胞:模拟合体滋养层发育和发病机制
  • 批准号:
    8560788
  • 财政年份:
    2013
  • 资助金额:
    $ 19.38万
  • 项目类别:
Pluripotent Stem Cells: Modeling syncytiotrophoblast development and pathogenesis
多能干细胞:模拟合体滋养层发育和发病机制
  • 批准号:
    8720806
  • 财政年份:
    2013
  • 资助金额:
    $ 19.38万
  • 项目类别:

相似海外基金

Angiogenic factors, abnormal placentation and adverse pregnancy outcomes
血管生成因素、异常胎盘和不良妊娠结局
  • 批准号:
    8927757
  • 财政年份:
    2014
  • 资助金额:
    $ 19.38万
  • 项目类别:
Angiogenic factors, abnormal placentation and adverse pregnancy outcomes
血管生成因素、异常胎盘和不良妊娠结局
  • 批准号:
    8441511
  • 财政年份:
    2012
  • 资助金额:
    $ 19.38万
  • 项目类别:
Angiogenic factors, abnormal placentation and adverse pregnancy outcomes
血管生成因素、异常胎盘和不良妊娠结局
  • 批准号:
    8626424
  • 财政年份:
    2012
  • 资助金额:
    $ 19.38万
  • 项目类别:
Angiogenic factors, abnormal placentation and adverse pregnancy outcomes
血管生成因素、异常胎盘和不良妊娠结局
  • 批准号:
    8240765
  • 财政年份:
    2012
  • 资助金额:
    $ 19.38万
  • 项目类别:
Analysis of the effect of oxidative stress on abnormal placentation
氧化应激对胎盘异常的影响分析
  • 批准号:
    23890101
  • 财政年份:
    2011
  • 资助金额:
    $ 19.38万
  • 项目类别:
    Grant-in-Aid for Research Activity Start-up
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