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:
    6752509
  • 负责人:
  • 金额:
    $ 26.98万
  • 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(申请人摘要):结直肠癌是第三先导

项目成果

期刊论文数量(0)
专著数量(0)
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专利数量(0)

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MARK R HELLMICH其他文献

MARK R HELLMICH的其他文献

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{{ 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:
    $ 26.98万
  • 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:
    $ 26.98万
  • 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:
    $ 26.98万
  • 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:
    $ 26.98万
  • 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:
    $ 26.98万
  • 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:
    $ 26.98万
  • 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:
    $ 26.98万
  • 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:
    $ 26.98万
  • 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:
    6332317
  • 财政年份:
    2001
  • 资助金额:
    $ 26.98万
  • 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:
    $ 26.98万
  • 项目类别:

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腓骨肌萎缩症蛋白 Mfn2 对钙通量和线粒体裂变的控制。
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