MOLECULAR BASIS OF ENTEROCYTE REGULATION DURING ONTOGENY

个体发育过程中肠细胞调节的分子基础

基本信息

  • 批准号:
    6164914
  • 负责人:
  • 金额:
    $ 15.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1998
  • 资助国家:
    美国
  • 起止时间:
    1998-03-01 至 2003-02-28
  • 项目状态:
    已结题

项目摘要

In this grant I propose to study the regulation of both the neonatal intestinal immunoglobulin receptors (fcRn) and polymeric receptor (pIgR) genes, as a model to understand small intestinal epithelial ontogeny and adaptation. The Fc receptor transports IgG from breast milk and is essential for establishing humoral immunity in the neonate. Located on the enterocytes apical membrane, FcRn transport IgG transcellulary to the basolateral membrane where its released into the systemic circulation. In contrast, pIgR transports IgA from the basolateral membrane to the lumen. In rodents, I have shown that both FcRn and pIgR regulation have a unique tissue, developmental and hormonal-pattern of expression. FcRn's expression is developmentally restricted to the suckling phase, during which time the transcript is produced in a proximodistal gradient, and is inhibited by corticosteroids administration. In contrast, pIgR mRNA levels are induced after warning, and may be further enhanced by corticosteroids. To begin addressing at a molecular level the mechanism underlying enterocyte regulation during development, the rat FcRn and murine pIgR genes have been cloned. We have done transient-transfection studies with an intestinal cell line, using chimeric constructs of either the 5' - flanking regions of the FcRn or pIgR genes fused to the reporter luciferase. Transfection of clones derived by nested deletions has been done, and has led to the identification of several activator and repressor regions that appear to modulate basal activity. Moreover, I will assess the response of each gene to corticosteroids using in vitro transfection experiments with cells containing chimeric constructs. Experiments with homologous and heterologous promoters will be used to define enhancer repressors elements, and DNase I footprint and electrophoretic gel mobility shift assays will be done to define the DNA-protein interaction. To enhance our ability to draw more physiologically relevant conclusions from our in vitro experiments, a transgenic mouse model is presented that appears to reflect FcRns normal pattern of expression. Similar lines will be developed with the pIgR 5'-flanking region to define the elements needed to control the genes in vivo expression. The projects long term objectives is to evaluate the transcriptional factor that regulates the intestinal and developmental-specific pattern of expression. Analysis of the FcRn and pIgR genes offers a unique model that may lead to a better understanding of the molecular mechanism of intestinal ontogeny, and specifically the intrinsic clock which controls its regulation.
在这项拨款中,我建议研究新生儿 肠免疫球蛋白受体(fcRn)和多聚体受体(pIgR) 基因,作为了解小肠上皮个体发育和 适应。 Fc受体从母乳中转运IgG, 对新生儿建立体液免疫至关重要。 位于 肠上皮细胞顶膜,FcRn转运IgG跨细胞, 基底外侧膜释放到全身 流通 相反,pIgR从基底外侧转运伊加, 膜到管腔。 在啮齿类动物中,我已经证明FcRn和pIgR 调节有一个独特的组织,发展和繁殖模式, 表情 FcRn的表达在发育上局限于 哺乳期,在此期间,转录本以 近远梯度,并被皮质类固醇抑制 局 相比之下,pIgR mRNA水平在 警告,并可能通过皮质类固醇进一步增强。 开始 在分子水平上探讨肠上皮细胞 在发育过程中的调控,大鼠FcRn和小鼠pIgR基因具有 被克隆了我们已经做了瞬时转染研究, 肠细胞系,使用5' - 与报告基因融合的FcRn或pIgR基因的侧翼区 荧光素酶 通过巢式缺失衍生的克隆的转染已经被证实。 做了,并导致了几个激活剂的识别, 阻遏物区域似乎调节基础活性。 而且我 将评估每个基因对皮质类固醇的反应, 用含有嵌合构建体的细胞进行转染实验。 使用同源和异源启动子的实验将用于 定义增强子阻遏物元件和DNA酶I足迹, 将进行电泳凝胶迁移率变动测定以确定 DNA-蛋白质相互作用 为了提高我们的能力, 从我们的体外实验中得出的生理学相关结论, 转基因小鼠模型似乎反映了FcRns 正常的表达方式。 类似的线路将与 pIgR 5 '-侧翼区,以限定控制免疫应答所需的元件。 基因在体内的表达。 该项目的长期目标是 评估调节肠和 发育特异性表达模式。 分析FcRn和 pIgR基因提供了一个独特的模型,可能会导致更好的理解 肠道个体发育的分子机制,特别是 控制其调节的内在时钟。

项目成果

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MARTIN G MARTIN其他文献

MARTIN G MARTIN的其他文献

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{{ truncateString('MARTIN G MARTIN', 18)}}的其他基金

Neurogenin3 and Intestinal Failure
Neurogenin3 和肠衰竭
  • 批准号:
    7872957
  • 财政年份:
    2009
  • 资助金额:
    $ 15.3万
  • 项目类别:
Neurogenin3 and Intestinal Failure
Neurogenin3 和肠衰竭
  • 批准号:
    7742655
  • 财政年份:
    2009
  • 资助金额:
    $ 15.3万
  • 项目类别:
Neurogenin3 and Intestinal Failure
Neurogenin3 和肠衰竭
  • 批准号:
    8114284
  • 财政年份:
    2009
  • 资助金额:
    $ 15.3万
  • 项目类别:
Neurogenin3 and Intestinal Failure
Neurogenin3 和肠衰竭
  • 批准号:
    7915874
  • 财政年份:
    2009
  • 资助金额:
    $ 15.3万
  • 项目类别:
Neurogenin3 and Intestinal Failure
Neurogenin3 和肠衰竭
  • 批准号:
    8303422
  • 财政年份:
    2009
  • 资助金额:
    $ 15.3万
  • 项目类别:
Neurogenin3 and Intestinal Failure
Neurogenin3 和肠衰竭
  • 批准号:
    8116064
  • 财政年份:
    2009
  • 资助金额:
    $ 15.3万
  • 项目类别:
Cell Fate Determination of the Intestine and Chronic Diarrhea in Children
儿童肠道和慢性腹泻的细胞命运测定
  • 批准号:
    7232449
  • 财政年份:
    2006
  • 资助金额:
    $ 15.3万
  • 项目类别:
Cell Fate Determination of Intestine/Chronic Diarrhea
肠道/慢性腹泻的细胞命运测定
  • 批准号:
    7080886
  • 财政年份:
    2006
  • 资助金额:
    $ 15.3万
  • 项目类别:
Regulation of Intestinal Nutrient Transporters
肠道营养转运蛋白的调节
  • 批准号:
    6368210
  • 财政年份:
    2001
  • 资助金额:
    $ 15.3万
  • 项目类别:
Regulation of Intestinal Nutrient Transporters
肠道营养转运蛋白的调节
  • 批准号:
    6536416
  • 财政年份:
    2001
  • 资助金额:
    $ 15.3万
  • 项目类别:

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Innate immune functions of the intracellular antibody receptor TRIM21
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基于 IgG 的单克隆抗体/受体相互作用的机制和工程
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  • 财政年份:
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基于 IgG 的单克隆抗体/受体相互作用的机制和工程
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探索性研究小额资助:通过抗体受体包被的磁囊和铁蛋白缀合物分离细胞和生物大分子
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