Proton sensing G protein coupled receptors and TRPC channels - novel players in neuronal proliferation and development

质子传感 G 蛋白偶联受体和 TRPC 通道 - 神经元增殖和发育的新参与者

• 批准号: BB/I008748/1
• 负责人: Maike Glitsch
• 金额: $ 44.66万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI008748%2F1
• 关键词: Proton; sensing; protein; coupled; receptors

In order for our human body to function properly, it has to offer a stable environment to its building blocks, the cells. Cells work best in a tightly controlled environment in which factors such as nutrient supply and pH are kept more or less constant. Any change in environmental settings may have detrimental effects on cell functioning and can even cause cell death. One of the parameters that is kept constant is the extracellular proton concentration that determines the tissue pH. A too low (acidic) extracellular pH (equivalent to a high extracellular proton concentration) has been shown to cause cell death. One such example for acidosis-induced cell death is cell loss following a stroke (ischemia). Surprisingly, however, under certain conditions a low external pH promotes rather than compromises cell survival. This astonishing observation has been made in cancerous tissue: here, extracellular acidosis is not only tolerated by cancer cells, but it is essential for cancer progression and formation of metastases. An equally intriguing finding is that the detrimental effects of ischemia (in large part due to acidosis of the ischemic tissue) is less dramatic and more readily reversible in younger compared with old patients. All this suggests that the ability of cells to respond to a low extracellular pH with enhanced survival rather than death may be cell-type specific and can to some extent depend on the developmental stage of the tissue involved. Cancers mimic early developmental stages of tissues in that both cancer cells and developing cells continually multiply to build up tissue mass. We have recently made the important observation that developing brain cells, just like cancer cells, respond to external acidification with increased cell survival rather than cell death. This surprise finding has led us to propose the following project: to investigate how a fall in extracellular pH promotes survival of normal, developing brain cells. This study is the first to address the effects of extracellular acidosis on developing tissue and will open up an entirely new field of research. Understanding the cellular mechanism triggered by a fall in external pH that induce cell survival in normal cells will provide important insights into how cancerous cells may take advantage of these pathways and use them to enhance survival of transformed as opposed to unftransformed cells. Ultimately, it may provide us with novel therapeutic strategies to combat debilitating diseases such as cancer, which affect 1 in 3 people.

为了使我们的人体正常运作，它必须为它的组成部分细胞提供一个稳定的环境。细胞在严格控制的环境中工作得最好，其中营养供应和pH值等因素或多或少保持恒定。环境设置的任何变化都可能对细胞功能产生不利影响，甚至可能导致细胞死亡。保持恒定的参数之一是决定组织pH的细胞外质子浓度。过低的（酸性）细胞外pH（相当于高细胞外质子浓度）已被证明会导致细胞死亡。酸中毒诱导的细胞死亡的一个这样的例子是中风（缺血）后的细胞损失。然而，令人惊讶的是，在某些条件下，低的外部pH促进而不是损害细胞存活。这一惊人的观察是在癌组织中发现的：在这里，细胞外酸中毒不仅能被癌细胞耐受，而且对癌症进展和转移的形成至关重要。一个同样有趣的发现是，与老年患者相比，年轻患者缺血的有害影响（很大程度上是由于缺血组织的酸中毒）不太明显，更容易逆转。所有这些都表明，细胞对低细胞外pH值做出反应并增强生存而不是死亡的能力可能是细胞类型特异性的，并且在一定程度上取决于所涉及组织的发育阶段。癌症模仿组织的早期发育阶段，因为癌细胞和发育中的细胞都不断繁殖以建立组织块。我们最近发现了一个重要的观察结果，即发育中的脑细胞，就像癌细胞一样，对外部酸化的反应是增加细胞存活而不是细胞死亡。这一令人惊讶的发现促使我们提出了以下项目：研究细胞外pH值的下降如何促进正常发育的脑细胞的存活。这项研究是第一个解决细胞外酸中毒对发育中组织的影响，并将开辟一个全新的研究领域。了解由外部pH值下降引发的细胞机制，诱导正常细胞中的细胞存活，将为癌细胞如何利用这些途径提供重要的见解，并利用它们来提高转化细胞的存活率，而不是未转化细胞。最终，它可能为我们提供新的治疗策略，以对抗癌症等使人衰弱的疾病，这些疾病影响三分之一的人。

项目成果

Functional expression of calcium-permeable canonical transient receptor potential 4-containing channels promotes migration of medulloblastoma cells.

• DOI: 10.1113/jp274659
• 发表时间: 2017-08-15
• 期刊: The Journal of physiology
• 作者: Wei WC;Huang WC;Lin YP;Becker EBE;Ansorge O;Flockerzi V;Conti D;Cenacchi G;Glitsch MD
• 通讯作者: Glitsch MD

Gordon Research Conference on Ca2+ Signalling 2017 Editorial.

戈登 Ca2 信号研究会议 2017 年社论。

• DOI: 10.1113/jp276271
• 发表时间: 2018
• 期刊: The Journal of physiology
• 作者: Glitsch MD