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
- 来源:
- 关键词:biomarkercalcium fluxcarcinogenesiscell growth regulationcholecystokinincolorectal neoplasmsgastrinsgenetically modified animalshormone receptorhuman tissuelaboratory mouseneoplastic growthneuropeptide receptorprotein isoformsprotein structure functionprotooncogenereceptor expressionreceptor sensitivitytissue /cell culturetransfection
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)
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
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:
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:
$ 26.98万 - 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:
$ 26.98万 - 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:
$ 26.98万 - 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:
$ 26.98万 - 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:
$ 26.98万 - 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:
$ 26.98万 - 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:
$ 26.98万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Master's