Studies of a Novel CCK-B/Gastrin Receptor Splice Variant

新型 CCK-B/胃泌素受体剪接变体的研究

基本信息

  • 批准号:
    6332317
  • 负责人:
  • 金额:
    $ 25.95万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2001
  • 资助国家:
    美国
  • 起止时间:
    2001-07-01 至 2006-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (Applicant's Abstract): Colorectal cancer is the third leading cause of cancer death in the United States, Colon carcinogenesis is a complex, multi-step process involving progressive changes in signaling pathways regulating intestinal epithelial cell proliferation, differentiation and programmed death. The peptide hormone, gastrin 1-17 (G-17), and its non-amidated precursor, glycine-extended gastrin (G-GIy), exert potent trophic effects on colon cancer cells. The long-term goal is to understand the role of these peptide hormones in the regulation of epithelial cell biology and colon carcinogenesis. Although the growth-promoting effect of these peptides on colon cancers has been extensively documented, the identity of the receptors and intracellular signaling pathways involved remain controversial. The investigators have identified and isolated the cDNA for a novel splice variant of the human cholecystokinin-B/gastrin receptor (CCK-BR), a member of the G protein-coupled receptor (GPCR) superfamily. The splice variant (designated CCK-BRi4sv for intron 4 containing splice variant) encodes a receptor protein containing 69 additional amino acid residues in its putative third intracellular loop domain. CCK-BRi4sv is expressed in adenomatous polyps and colorectal cancers, but not in nonmalignant colonic mucosa adjacent to the cancer. Mouse Balb3T3 cells expressing the splice variant exhibited spontaneous, ligand-independent, oscillatory, increases in [Ca2+]i whereas, the same cells expressing wild-type CCK-BR (CCK-BRwt) did not. Similarly, primary cultures of human cells isolated from freshly resected colorectal cancers exhibited, ligand-independent, oscillatory increases in [Ca2+]. For both Balb3T3 and primary tumor cells, application of G-17 (10 and 200 nM, respectively) caused an increase in [Ca2+]i. Selective CCK-BR antagonists blocked the G- 17-stimulated Ca2+ responses, but not the spontaneous [Ca2+]i oscillations. In addition to spontaneous intracellular signaling, BaIb3T3 cells expressing CCK-BRi4sv exhibited an increased rate of cell proliferation (approximately 2.5-fold), in the absence of G-17, compared to cells expressing wild-type CCK-BR (CCK-BRwt). Based on these findings, the PI hypothesizes that CCK-BRi4sv may regulate colorectal cancer cell growth through both a gastrin-independent and -dependent mechanism and thus play a significant role in colorectal carcinogenesis. Furthermore, the PI hypothesizes that the function of CCK-BRi4sv in colorectal cancer biology is a direct consequence of the structural changes in the third intracellular loop domain, caused by intron retention, and the impact of those changes on intracellular signal transduction. To examine these hypotheses they plan experiments with the following specific aims: 1) to determine the spatial and temporal expression of the CCK-BR splice variant in adenomatous polyps and colon cancers; 2) to determine the effects of intron retention on receptor-mediated intracellular signal transduction and receptor desensitization/internalization; and 3) to determine the effects of ectopic expression of the CCK-BR splice variant on colonic epithelial cell homeostasis and susceptibility to carcinogen-induced colon cancer using a transgenic mouse model. These studies will provide important and new information regarding the role of the novel receptor splice variant and G-17 and G-Gly in epithelial cell biology and colon carcinogenesis. Furthermore, these studies may, in the future, provide the basis for the development of innovative therapeutic strategies for the treatment of peptide hormone-sensitive cancers.
描述(申请人的摘要):结肠直肠癌是第三大主要的癌症。 在美国癌症死亡的原因中,结肠癌的发生是一个复杂的, 涉及信号传导途径渐进变化的多步骤过程 调节肠上皮细胞增殖、分化和 程序化死亡肽激素胃泌素1-17(G-17)及其 非酰胺化的前体甘氨酸延伸的胃泌素(G-Gly), 对结肠癌细胞的影响。长期目标是了解 这些肽激素在调节上皮细胞生物学和结肠 致癌作用虽然这些肽对结肠的生长促进作用 癌症已经被广泛记录,受体的身份和 涉及的细胞内信号传导途径仍然存在争议。的 研究人员已经鉴定并分离出一种新的剪接变异体的cDNA 人胆囊收缩素-B/胃泌素受体(CCK-BR)是G 蛋白偶联受体(GPCR)超家族。剪接变体(命名为 CCK-BRi 4sv(含内含子4的剪接变体)编码受体蛋白 在其推定的第三个氨基酸残基中含有69个额外的氨基酸残基, 胞内环结构域。CCK-BRi 4sv在腺瘤性息肉中表达, 结直肠癌,但不是在邻近的非恶性结肠粘膜 癌表达剪接变体的小鼠Balb 3 T3细胞表现出 自发的,不依赖配体的,振荡的,[Ca 2 +]i增加,而 表达野生型CCK-BR(CCK-BRwt)的相同细胞则没有。同样,主要 从新鲜切除的结肠直肠癌中分离的人细胞培养物 表现出,配体非依赖性,振荡增加[Ca 2 +]。为 Balb 3 T3和原代肿瘤细胞,应用G-17(10和200 nM, [Ca 2 +]i增加。选择性CCK-BR拮抗剂 阻断G- 17刺激的Ca ~(2+)反应,但不能阻断自发性[Ca ~(2+)]i 振荡除了自发的细胞内信号传导,BaIb 3 T3细胞 表达CCK-BRi 4sv的细胞增殖速率增加, (约2.5倍),与表达G-17的细胞相比, 野生型CCK-BR(CCK-BRwt)。基于这些发现,PI假设, CCK-BRi 4sv可能通过两种途径调节结直肠癌细胞的生长, 胃泌素非依赖性和依赖性机制,从而发挥重要作用 在结肠直肠癌发生中的作用此外,PI假设 CCK-BRi 4sv在结直肠癌生物学中的功能是 内含子引起的第三胞内环结构域的结构变化 以及这些变化对细胞内信号的影响 转导为了检验这些假设,他们计划用 以下具体目标:1)确定空间和时间表达的 腺瘤性息肉和结肠癌中CCK-BR剪接变异体; 2) 确定内含子保留对受体介导的细胞内 信号转导和受体脱敏/内化;和3) 确定CCK-BR剪接变体的异位表达对 结肠上皮细胞稳态和致癌物诱导的易感性 使用转基因小鼠模型的结肠癌。这些研究将提供 关于新受体剪接作用的重要和新信息 G-17和G-Gly在上皮细胞生物学和结肠癌发生中的作用。 此外,这些研究可能会在未来提供基础, 开发用于治疗肽的创新治疗策略 敏感性癌症。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

MARK R HELLMICH其他文献

MARK R HELLMICH的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('MARK R HELLMICH', 18)}}的其他基金

UTMB Clinical and Translational Science Award
UTMB 临床和转化科学奖
  • 批准号:
    9270638
  • 财政年份:
    2015
  • 资助金额:
    $ 25.95万
  • 项目类别:
NRSA Training Core
NRSA 培训核心
  • 批准号:
    10101759
  • 财政年份:
    2015
  • 资助金额:
    $ 25.95万
  • 项目类别:
UTMB Clinical and Translational Science Award
UTMB 临床和转化科学奖
  • 批准号:
    9128785
  • 财政年份:
    2015
  • 资助金额:
    $ 25.95万
  • 项目类别:
UTMB Clinical and Translational Science Award
UTMB 临床和转化科学奖
  • 批准号:
    9085702
  • 财政年份:
    2015
  • 资助金额:
    $ 25.95万
  • 项目类别:
Role of Hydrogen Sulfide in Colorectal Tumors
硫化氢在结直肠肿瘤中的作用
  • 批准号:
    9079450
  • 财政年份:
    2014
  • 资助金额:
    $ 25.95万
  • 项目类别:
Role of Hydrogen Sulfide in Colorectal Tumors
硫化氢在结直肠肿瘤中的作用
  • 批准号:
    8708260
  • 财政年份:
    2014
  • 资助金额:
    $ 25.95万
  • 项目类别:
CORE--PEPTIDE RECEPTOR CORE LABORATORY
核心--肽受体核心实验室
  • 批准号:
    6907132
  • 财政年份:
    2005
  • 资助金额:
    $ 25.95万
  • 项目类别:
Studies of a Novel CCK-B/Gastrin Receptor Splice Variant
新型 CCK-B/胃泌素受体剪接变体的研究
  • 批准号:
    6896603
  • 财政年份:
    2001
  • 资助金额:
    $ 25.95万
  • 项目类别:
Studies of a Novel CCK-B/Gastrin Receptor Splice Variant
新型 CCK-B/胃泌素受体剪接变体的研究
  • 批准号:
    6517796
  • 财政年份:
    2001
  • 资助金额:
    $ 25.95万
  • 项目类别:
Studies of a Novel CCK-B/Gastrin Receptor Splice Variant
新型 CCK-B/胃泌素受体剪接变体的研究
  • 批准号:
    6752509
  • 财政年份:
    2001
  • 资助金额:
    $ 25.95万
  • 项目类别:

相似海外基金

Control of calcium flux and mitochondrial fission by the Charcot Marie Tooth disease protein Mfn2.
腓骨肌萎缩症蛋白 Mfn2 对钙通量和线粒体裂变的控制。
  • 批准号:
    10322143
  • 财政年份:
    2021
  • 资助金额:
    $ 25.95万
  • 项目类别:
Control of calcium flux and mitochondrial fission by the Charcot Marie Tooth disease protein Mfn2.
腓骨肌萎缩症蛋白 Mfn2 对钙通量和线粒体裂变的控制。
  • 批准号:
    10154169
  • 财政年份:
    2021
  • 资助金额:
    $ 25.95万
  • 项目类别:
Control of calcium flux and mitochondrial fission by the Charcot Marie Tooth disease protein Mfn2.
腓骨肌萎缩症蛋白 Mfn2 对钙通量和线粒体裂变的控制。
  • 批准号:
    10540812
  • 财政年份:
    2021
  • 资助金额:
    $ 25.95万
  • 项目类别:
Purinergic control of calcium flux in podocytes
足细胞钙流的嘌呤能控制
  • 批准号:
    9552989
  • 财政年份:
    2018
  • 资助金额:
    $ 25.95万
  • 项目类别:
Purinergic control of calcium flux in podocytes
足细胞钙流的嘌呤能控制
  • 批准号:
    10292941
  • 财政年份:
    2018
  • 资助金额:
    $ 25.95万
  • 项目类别:
Purinergic control of calcium flux in podocytes
足细胞钙流的嘌呤能控制
  • 批准号:
    10047722
  • 财政年份:
    2018
  • 资助金额:
    $ 25.95万
  • 项目类别:
Boron accelerates cultured osteoblastic cell activity through calcium flux
硼通过钙流加速培养的成骨细胞活性
  • 批准号:
    25670812
  • 财政年份:
    2013
  • 资助金额:
    $ 25.95万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Claudin 12 mediates paracellular calcium flux between opossum kidney cell monolayers
Claudin 12 介导负鼠肾细胞单层之间的细胞旁钙通量
  • 批准号:
    240882
  • 财政年份:
    2011
  • 资助金额:
    $ 25.95万
  • 项目类别:
Molecules & Mechanisms Mediating Proximal Tubular Calcium Flux
分子
  • 批准号:
    244633
  • 财政年份:
    2011
  • 资助金额:
    $ 25.95万
  • 项目类别:
    Salary Programs
Mercury induced disruptions of cellular calcium flux in paired neurons from lymnaea affect synaptic transmission and elicit apoptosis
汞诱导的成对神经元中细胞钙通量的破坏影响突触传递并引发细胞凋亡
  • 批准号:
    348881-2007
  • 财政年份:
    2007
  • 资助金额:
    $ 25.95万
  • 项目类别:
    Alexander Graham Bell Canada Graduate Scholarships - Master's
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了