CALCIUM REGULATION OF cAMP-DEPENDENT PROLIFERATION
营依赖性增殖的钙调节
基本信息
- 批准号:7070151
- 负责人:
- 金额:$ 20.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-09-30 至 2010-08-31
- 项目状态:已结题
- 来源:
- 关键词:autosomal dominant traitautosomal recessive traitcalcium fluxcalcium metabolismcell growth regulationcell proliferationcyclic AMPenzyme activitygene expressiongene mutationgenetic disorderhormone inhibitorhormone receptorhuman tissuekidney pharmacologymitogen activated protein kinasemolecular pathologyphenotypepodocytepolycystic kidneyprotein kinaserenal tubulestimulant /agonisttissue /cell culturevasopressins
项目摘要
Polycystic kidney diseases (PKDs) are lethal, hereditary disorders characterized by hyperplasia of the tubule epithelium, cyst formation and massive kidney enlargement. cAMP agonists, including arginine vasopressin, accelerate the proliferation of epithelial cells from PKD cysts but not from normal human kidneys (NHK). We discovered that cAMP activates extracellular signal-regulated kinases1/2[2] (ERK) in human PKD, but inhibits ERK activation in NHK cells. The molecular mechanisms underlying this phenotypic difference between PKD and NHK cells are linked to cAMP/ protein kinase A-dependent B-Raf activation of MEK and ERK, leading to increased cell proliferation. Recent studies in animals with four different genetic types of PKD showed that inhibition of renal cAMP production by vasopressin V2 receptor antagonist OPC-31260 dramatically halted cyst and kidney enlargement, demonstrating a central role for
cAMP in renal cystic disease. Mutated gene products of hereditary cystic disorders are thought to cause abnormal Ca2+ levels in renal tubule cells. Recently, we found that inhibition of Ca2+ entry in mouse cortical collecting duct cells (M-1) with channel blockers or reduced extracellular [Ca2+] caused a phenotypic switch in the proliferation response to cAMP. cAMP inhibited the proliferation of M-1 cells with normal intracellular [Ca2+]; however, in M-1 cells with reduced [Ca2+] cAMP stimulated B-Raf, the MEK-ERK pathway and cell proliferation, mimicking the PKD phenotype. The central hypothesis is that in human ADPKD and ARPKD, dysfunctional Ca2+ metabolism by renal epithelial cells induces and maintains a "phenotypic switch" that
uncovers a common cellular pathway leading to cAMP-dependent activation of B-Raf and ERK, and increased cell proliferation. The strength of this proposal is the use of cyst epithelial cells from two different types of human hereditary disease, ADPKD and ARPKD, to address the following specific aims: Aim 1: Determine if [Ca2+]i modifies cAMP-dependent B-Raf signaling through the MEK-ERK pathway and contributes to the phenotypic difference in between PKD and NHK cells in the cAMP mitogenic response. Aim 2. Elucidate mechanisms by which vasopressin V2 receptor agonists and antagonists adjust intracellular Ca2+ and modulate cAMP-dependent B-Raf activation and the proliferation of human PKD cells. Aim 3. Determine if selective reduction of B-Raf abundance and inhibition of B-Raf kinase activity diminish cAMP-dependent ERK activation and cell proliferation in PKD cells. The results from these studies will provide fundamentally new opportunities for developing novel small molecule therapies to slow, and possibly halt the progression of PKD in patients.
多囊肾脏疾病(PKD)是致命的,遗传性疾病为特征,其特征是小管上皮的增生,囊肿形成和大量的肾脏肿大。包括精氨酸加压素在内的营地激动剂加速了来自PKD囊肿的上皮细胞的增殖,但不能从正常的人肾脏(NHK)加速。我们发现CAMP激活了人类PKD中细胞外信号调节的激酶1/2 [2](ERK),但会抑制NHK细胞中的ERK激活。 PKD和NHK细胞之间这种表型差异的分子机制与MEK和ERK的CAMP/蛋白激酶A依赖性B-RAF激活有关,从而导致细胞增殖增加。在具有四种不同遗传类型的PKD的动物的最新研究表明,加压素V2受体拮抗剂OPC-31260抑制肾脏cAMP的产生,急剧停止了囊肿和肾脏增大,这表明了核心的核心作用
肾脏囊性疾病的营地。遗传性囊性疾病的突变基因产物被认为在肾小管细胞中引起异常Ca2+水平。最近,我们发现在小鼠皮质收集管细胞(M-1)中,Ca2+进入通道阻滞剂或细胞外[Ca2+]的抑制作用在对cAMP的增殖反应中引起了表型转换。 CAMP抑制了正常细胞内的M-1细胞的增殖[Ca2+];但是,在减少[Ca2+] cAMP降低的M-1细胞中,MEK-ERK途径和细胞增殖,模仿PKD表型。中心假设是,在人ADPKD和ARPKD中,肾上皮细胞的功能障碍Ca2+代谢功能障碍可引起并保持“表型转换”,以
发现一种常见的细胞途径,导致B-RAF和ERK的cAMP依赖性激活,并增加细胞增殖。 The strength of this proposal is the use of cyst epithelial cells from two different types of human hereditary disease, ADPKD and ARPKD, to address the following specific aims: Aim 1: Determine if [Ca2+]i modifies cAMP-dependent B-Raf signaling through the MEK-ERK pathway and contributes to the phenotypic difference in between PKD and NHK cells in the cAMP mitogenic response. AIM 2。阐明加压素V2受体激动剂和拮抗剂调节细胞内Ca2+的机制,并调节cAMP依赖性B-RAF激活以及人PKD细胞的增殖。目标3。确定B-RAF丰度的选择性降低和B-RAF激酶活性的抑制是否减少了PKD细胞中cAMP依赖性ERK激活和细胞增殖。这些研究的结果将为开发新型的小分子疗法的新机会提供新的机会,以减慢患者的速度,并可能停止患者的PKD进展。
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 }}
DARREN P. WALLACE其他文献
DARREN P. WALLACE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('DARREN P. WALLACE', 18)}}的其他基金
Kansas PKD Research and Translation Core Center
堪萨斯 PKD 研究与翻译核心中心
- 批准号:
10475035 - 财政年份:2020
- 资助金额:
$ 20.21万 - 项目类别:
Biomedical Research Core 1 - Biomarkers, Biomaterials, and Cellular Models Core
生物医学研究核心 1 - 生物标志物、生物材料和细胞模型核心
- 批准号:
10475041 - 财政年份:2020
- 资助金额:
$ 20.21万 - 项目类别:
Biomedical Research Core 1 - Biomarkers, Biomaterials, and Cellular Models Core
生物医学研究核心 1 - 生物标志物、生物材料和细胞模型核心
- 批准号:
10214614 - 财政年份:2020
- 资助金额:
$ 20.21万 - 项目类别:
Additional Informatics support on U54 Clinical Core
U54 临床核心的附加信息学支持
- 批准号:
10890529 - 财政年份:2020
- 资助金额:
$ 20.21万 - 项目类别:
Biomedical Research Core 1 - Biomarkers, Biomaterials, and Cellular Models Core
生物医学研究核心 1 - 生物标志物、生物材料和细胞模型核心
- 批准号:
10059766 - 财政年份:2020
- 资助金额:
$ 20.21万 - 项目类别:
Kansas PKD Research and Translation Core Center
堪萨斯 PKD 研究与翻译核心中心
- 批准号:
10686046 - 财政年份:2020
- 资助金额:
$ 20.21万 - 项目类别:
Biomedical Research Core 1 - Biomarkers, Biomaterials, and Cellular Models Core
生物医学研究核心 1 - 生物标志物、生物材料和细胞模型核心
- 批准号:
10686060 - 财政年份:2020
- 资助金额:
$ 20.21万 - 项目类别:
Additional informatics support on U54 Clinical Core
U54 临床核心的附加信息学支持
- 批准号:
10685724 - 财政年份:2020
- 资助金额:
$ 20.21万 - 项目类别:
相似海外基金
Development of CRISPR/Cas9-based exon-skipping strategies for the treatment of USH-associated deafness
开发基于 CRISPR/Cas9 的外显子跳跃策略来治疗 USH 相关耳聋
- 批准号:
10445638 - 财政年份:2022
- 资助金额:
$ 20.21万 - 项目类别:
Development of CRISPR/Cas9-based exon-skipping strategies for the treatment of USH-associated deafness
开发基于 CRISPR/Cas9 的外显子跳跃策略来治疗 USH 相关耳聋
- 批准号:
10688070 - 财政年份:2022
- 资助金额:
$ 20.21万 - 项目类别:
Endoplasmic Reticulum stress and thyroid cell death
内质网应激和甲状腺细胞死亡
- 批准号:
10595662 - 财政年份:2022
- 资助金额:
$ 20.21万 - 项目类别:
Endoplasmic Reticulum stress and thyroid cell death
内质网应激和甲状腺细胞死亡
- 批准号:
10414536 - 财政年份:2022
- 资助金额:
$ 20.21万 - 项目类别:
Structure-Function Relationships in Stargardt Disease.
Stargardt 病的结构-功能关系。
- 批准号:
10489833 - 财政年份:2021
- 资助金额:
$ 20.21万 - 项目类别: