Nitrergic relaxation in the gastrointestinal tract of mice with cell-specific deletion of NO-sensitive guanylyl cyclase

NO敏感鸟苷酸环化酶细胞特异性缺失小鼠胃肠道的氮能松弛

• 批准号: 5424209
• 负责人: Professor Dr. Andreas Friebe
• 金额: --
• 依托单位: Physiologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2004
• 资助国家: 德国
• 起止时间: 2003-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5424209?language=en
• 关键词: Nitrergic; relaxation; gastrointestinal; tract; mice

NO-sensitive guanylyl cyclase (NO-GC) catalyzes the generation of the intracellular second messenger cGMP. The enzyme plays a key role within NO/cGMP signalling. Being the most important receptor for the signal molecule nitric oxide, NO-GC participates in the regulation of many different physiological functions.We have generated mice which lack NO-GC ubiquitously. These mice are hypertensive, suffer from gastrointestinal dysmotility and die prematurely. The exact identity of the cells/tissues responsible for the individual phenotypes remains to be resolved.The reduced GI motility in the general GCKO mice can be explained by the loss of nitrergic relaxation. The exact mechanism of nitrergic relaxation has not been investigated thoroughly. It is currently being heavily discussed in the field whether neuronally released NO acts to relax smooth muscle cells (SMC) directly (similar to the action of endothelial NO in the vascular system) or whether interstitial cells of Cajal (ICC) are interposed to mediate nitrergic relaxation. In addition, a third cell type called 'fibroblast-like cell' with high NO-GC expression has been identified.We have already generated KO mice in which NO-GC is deleted specifically in SMC or in ICC. Nitrergic relaxation of GI tissue is moderately affected in the two single knockouts. A double mutant carrying a deletion of NO-GC in both SMC and ICC shows strong reduction of GI motility and an almost total lack of nitrergic relaxation. In this project, we would like to generate mice that lack NO-GC in FLC; in addition, we will generate double and triple mutants. Organ bath experiments and measurements of membrane potential including inhibitory junction potentials will be performed. With the help of these mice lacking the NO receptor in the most important NO-GC expressing cells in the gut, we will investigate the interplay of these cells and identify the exact mechanism of nitrergic relaxation.

NO-GC催化细胞内第二信使cGMP的产生。该酶在NO/cGMP信号转导中起关键作用。作为信号分子一氧化氮最重要的受体，NO-GC参与多种不同生理功能的调节，我们产生了普遍缺乏NO-GC的小鼠。这些小鼠患有高血压，患有胃肠动力障碍，并过早死亡。负责单个表型的细胞/组织的确切身份仍有待解决。一般GCKO小鼠的胃肠动力下降可以用氮能松弛的丧失来解释。氮能松弛的确切机制还没有得到彻底的研究。目前，神经释放的NO是否直接作用于平滑肌细胞(SMC)(类似于血管系统中内皮细胞的作用)，或者是否由Cajal间质细胞(ICC)介导的氮能松弛，目前在该领域引起了广泛的讨论。此外，还发现了一种高表达NO-GC的细胞类型，称为成纤维细胞样细胞。我们已经产生了在SMC或ICC中特异性缺失NO-GC的KO小鼠。在两个单一基因敲除中，胃肠道组织的氮能松弛受到中度影响。在SMC和ICC中同时携带NO-GC缺失的双突变体表现出强烈的胃肠动力降低和几乎完全缺乏硝能松弛。在这个项目中，我们希望在FLC中产生缺乏非GC的小鼠；此外，我们还将产生双重和三重突变。将进行器官浴实验和包括抑制连接电位在内的膜电位的测量。在这些在肠道中最重要的NO-GC表达细胞中缺乏NO受体的小鼠的帮助下，我们将研究这些细胞之间的相互作用，并确定氮能松弛的确切机制。

项目成果

Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity

• DOI: 10.1038/ncomms2626
• 发表时间: 2013-03-01
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Klein, Sabine;Seidler, Barbara;Saur, Dieter
• 通讯作者: Saur, Dieter

CrossTalk proposal: Interstitial cells are involved and physiologically important in neuromuscular transmission in the gut

CrossTalk 提案：间质细胞参与肠道神经肌肉传递，并且在生理上很重要

• DOI: 10.1113/jp271600
• 发表时间: 2016
• 期刊: The Journal of Physiology
• 作者: Sanders KM;Ward SM;Friebe A
• 通讯作者: Friebe A

Nitrergic signalling via interstitial cells of Cajal regulates motor activity in murine colon

• DOI: 10.1113/jp270511
• 发表时间: 2015-10-15
• 期刊: JOURNAL OF PHYSIOLOGY-LONDON
• 影响因子: 5.5
• 作者: Lies, Barbara;Beck, Katharina;Friebe, Andreas
• 通讯作者: Friebe, Andreas

Dominant role of interstitial cells of Cajal in nitrergic relaxation of murine lower oesophageal sphincter

• DOI: 10.1113/jphysiol.2014.273540
• 发表时间: 2015-01-15
• 期刊: JOURNAL OF PHYSIOLOGY-LONDON
• 影响因子: 5.5
• 作者: Groneberg, Dieter;Zizer, Eugen;Friebe, Andreas
• 通讯作者: Friebe, Andreas

Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma

• DOI: 10.1073/pnas.1524398113
• 发表时间: 2016-04-26
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Ghosh, Arnab;Koziol-White, Cynthia J.;Stuehr, Dennis J.
• 通讯作者: Stuehr, Dennis J.