Calcium Dynamics in Interstitial Cells of Cajal

Cajal 间质细胞中的钙动态

基本信息

  • 批准号:
    8290442
  • 负责人:
  • 金额:
    $ 32.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2000
  • 资助国家:
    美国
  • 起止时间:
    2000-04-01 至 2014-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The control of gastrointestinal (GI) motility requires a complex interaction between several cell types such as smooth muscle and enteric nerves. In recent years we have added interstitial cells of Cajal (ICC) to this complex system. ICC regulate smooth muscle function and loss of ICC is associated with several motility disorders. ICC networks are constantly turning over and maintenance of the networks requires tight regulation of ICC proliferation. Ano-1, a Ca2+ activated Cl- channel has recently been found to be selectively expressed on ICC in the muscle layers of the gut as well as in several tumors, including gastrointestinal stromal tumors. The overall objective of this proposal is to determine the role of Ano1 in ICC function. The central hypothesis of this proposal is that Ano-1 has dual, novel roles in ICC physiology. It acts as a key molecule in the regulation of ICC proliferation and as an ion channel required for the repolarization of the slow wave. The central hypothesis will be tested in two specific aims. Specific Aim 1 will test the hypothesis that Ano1 regulates proliferation of ICC and Specific aim 2 will test the hypothesis that Ano1 is required for repolarization of the slow wave. The first specific aim is supported by preliminary data that show that Ano1 in the tunica muscularis is expressed only on ICC, that Ano1 may be used to detect loss of ICC in motility disorders, that a lack of Ano1 is associated with a decrease in proliferation of ICC and that an increase in expression of Ano-1 is associated with an increase in ICC proliferation. The preliminary data also provide evidence, from bioinformatics analysis of microarray data comparing knockout to wild type mice, that key molecules associated with the control of proliferation, including CDK1/cdc2, are down-regulated when Ano1 is absent. The second specific aim is supported by preliminary data that show that Cl- channel blockers alter the duration of the plateau of the slow wave, that the slow wave is prolonged when Ano-1 expression is decreased and that it normalizes after Ano-1 is expressed. The PI will test the central hypothesis by a combination of innovative techniques including 3D reconstructions of immunohistochemical data, Western blots, RT-PCR, single cell PCR, quantitative PCR, lentivirus and si/shRNA knock down techniques, electroporation, knockout mice, organotypic and single cell cultures, bioinformatic analysis of microarray data, proteomics, Ca2+ and Cl- imaging, microelectrode recordings and patch clamp techniques. Successful completion of the proposed studies has both basic significance and clinical impact. Our work on the newly discovered protein Ano1 will provide mechanistic information on both how ICC networks are maintained and on the regulation of the slow wave. Of immediate clinical significance our work will inform clinicians and pathologists on use of antibodies to Ano1 to assess ICC in motility disorders and provide targets for future therapeutic interventions. Our work also has broad implications beyond the GI tract. As Ano-1 is expressed in many organs and tumors including gastrointestinal stromal tumors, our findings will likely apply to several other organs outside of the GI tract. PUBLIC HEALTH RELEVANCE: Gastrointestinal motility disorders are common and associated with considerable morbidity and mortality. A recent finding is that a key cell type, the interstitial cells of Cajal (ICC) is required for normal gastrointestinal motility and is lost in several of these disorders. This proposal will investigate the role of a newly discovered protein, Ano1, in the control of ICC function, including the control of ICC numbers, which may lead to new strategies to replace the lost or damaged ICC and restore normal gastrointestinal motility.
描述(由申请人提供):胃肠道运动的控制需要几种细胞类型(如平滑肌和肠神经)之间复杂的相互作用。近年来,我们在这个复杂的系统中加入了Cajal间质细胞(ICC)。ICC调节平滑肌功能,ICC的丧失与几种运动障碍有关。国际商会网络不断更新换代,维护网络需要严格监管国际商会的扩散。Ano-1,一个Ca2+激活的Cl-通道,最近被发现在肠肌层的ICC上选择性表达,以及在一些肿瘤中,包括胃肠道间质瘤。该提案的总体目标是确定Ano1在ICC功能中的作用。该提案的中心假设是,Ano-1在ICC生理学中具有双重的新作用。它是调控ICC增殖的关键分子,也是慢波复极化所需的离子通道。中心假设将在两个具体目标中得到检验。特异性目标1将测试Ano1调节ICC增殖的假设,特异性目标2将测试Ano1是慢波复极化所必需的假设。第一个具体目的得到了初步数据的支持,这些数据表明,肌膜中的Ano1仅在ICC上表达,Ano1可用于检测运动障碍中ICC的缺失,Ano1的缺乏与ICC增殖的减少有关,Ano1表达的增加与ICC增殖的增加有关。通过对基因敲除小鼠与野生型小鼠的生物信息学分析,初步数据还提供了证据,表明当Ano1缺失时,与增殖控制相关的关键分子,包括CDK1/cdc2,均下调。第二个具体目标得到了初步数据的支持,这些数据表明Cl通道阻滞剂改变慢波平台期的持续时间,当Ano-1表达减少时慢波延长,而在Ano-1表达后慢波正常化。PI将通过创新技术的组合来检验中心假设,包括免疫组织化学数据的3D重建、Western blots、RT-PCR、单细胞PCR、定量PCR、慢病毒和si/shRNA敲除技术、电穿孔、敲除小鼠、器官型和单细胞培养、微阵列数据的生物信息学分析、蛋白质组学、Ca2+和Cl-成像、微电极记录和膜片钳技术。本研究的成功完成既有基础意义又有临床意义。我们对新发现的Ano1蛋白的研究将提供有关ICC网络如何维持和慢波调节的机制信息。具有直接临床意义的是,我们的工作将告知临床医生和病理学家使用Ano1抗体来评估运动障碍中的ICC,并为未来的治疗干预提供目标。我们的工作还具有胃肠道以外的广泛意义。由于Ano-1在包括胃肠道间质瘤在内的许多器官和肿瘤中表达,我们的发现可能适用于胃肠道外的其他器官。

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 }}

GIANRICO FARRUGIA其他文献

GIANRICO FARRUGIA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('GIANRICO FARRUGIA', 18)}}的其他基金

Pathophysiology of Diabetic Gastroparesis
糖尿病胃轻瘫的病理生理学
  • 批准号:
    10403596
  • 财政年份:
    2021
  • 资助金额:
    $ 32.4万
  • 项目类别:
Pathophysiology of Diabetic Gastroparesis
糖尿病胃轻瘫的病理生理学
  • 批准号:
    10618295
  • 财政年份:
    2021
  • 资助金额:
    $ 32.4万
  • 项目类别:
Pathobiology of Diabetic Gastroenteropathy
糖尿病胃肠病的病理学
  • 批准号:
    7456509
  • 财政年份:
    2007
  • 资助金额:
    $ 32.4万
  • 项目类别:
Pathobiology of Diabetic Gastroenteropathy
糖尿病胃肠病的病理学
  • 批准号:
    6848503
  • 财政年份:
    2004
  • 资助金额:
    $ 32.4万
  • 项目类别:
Pathobiology of the Enteric System
肠道系统病理学
  • 批准号:
    8685957
  • 财政年份:
    2004
  • 资助金额:
    $ 32.4万
  • 项目类别:
CALCIUM DYNAMICS IN INTERSTITIAL CELLS OF CAJAL
CAJAL 间质细胞中的钙动力学
  • 批准号:
    6381720
  • 财政年份:
    2000
  • 资助金额:
    $ 32.4万
  • 项目类别:
CALCIUM DYNAMICS IN INTERSTITIAL CELLS OF CAJAL
CAJAL 间质细胞中的钙动力学
  • 批准号:
    6727510
  • 财政年份:
    2000
  • 资助金额:
    $ 32.4万
  • 项目类别:
Calcium Dynamics in Interstitial Cells of Cajal
Cajal 间质细胞中的钙动态
  • 批准号:
    10425251
  • 财政年份:
    2000
  • 资助金额:
    $ 32.4万
  • 项目类别:
Calcium Dynamics in Interstitial Cells of Cajal
Cajal 间质细胞中的钙动态
  • 批准号:
    7643917
  • 财政年份:
    2000
  • 资助金额:
    $ 32.4万
  • 项目类别:
Calcium Dynamics in Interstitial Cells of Cajal
Cajal 间质细胞中的钙动态
  • 批准号:
    8063209
  • 财政年份:
    2000
  • 资助金额:
    $ 32.4万
  • 项目类别:

相似海外基金

University of Aberdeen and Vertebrate Antibodies Limited KTP 23_24 R1
阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
  • 批准号:
    10073243
  • 财政年份:
    2024
  • 资助金额:
    $ 32.4万
  • 项目类别:
    Knowledge Transfer Partnership
Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease
天然抗体和 B1 细胞在纤维增生性肺病中的作用
  • 批准号:
    10752129
  • 财政年份:
    2024
  • 资助金额:
    $ 32.4万
  • 项目类别:
CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies
职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
  • 批准号:
    2339201
  • 财政年份:
    2024
  • 资助金额:
    $ 32.4万
  • 项目类别:
    Continuing Grant
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
  • 批准号:
    MR/Y008693/1
  • 财政年份:
    2024
  • 资助金额:
    $ 32.4万
  • 项目类别:
    Research Grant
Developing first-in-class aggregation-specific antibodies for a severe genetic neurological disease
开发针对严重遗传神经系统疾病的一流聚集特异性抗体
  • 批准号:
    10076445
  • 财政年份:
    2023
  • 资助金额:
    $ 32.4万
  • 项目类别:
    Grant for R&D
Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model
发现中枢神经系统脱髓鞘疾病中的新型节点抗体并通过视神经脱髓鞘模型阐明其机制
  • 批准号:
    23K14783
  • 财政年份:
    2023
  • 资助金额:
    $ 32.4万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms controlling the physicochemical properties and functions of supercharged antibodies and development of their applications
阐明控制超电荷抗体的理化性质和功能的机制及其应用开发
  • 批准号:
    23KJ0394
  • 财政年份:
    2023
  • 资助金额:
    $ 32.4万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Role of antibodies in hepatitis E virus infection
抗体在戊型肝炎病毒感染中的作用
  • 批准号:
    10639161
  • 财政年份:
    2023
  • 资助金额:
    $ 32.4万
  • 项目类别:
Defining the protective or pathologic role of antibodies in Post-Ebola Syndrome
定义抗体在埃博拉后综合症中的保护或病理作用
  • 批准号:
    10752441
  • 财政年份:
    2023
  • 资助金额:
    $ 32.4万
  • 项目类别:
Human CMV monoclonal antibodies as therapeutics to inhibit virus infection and dissemination
人 CMV 单克隆抗体作为抑制病毒感染和传播的治疗药物
  • 批准号:
    10867639
  • 财政年份:
    2023
  • 资助金额:
    $ 32.4万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了