Mechanisms, consequences and regulation of pH non-uniformity in 3-D tissue structures: implications on cancer therapy

3-D 组织结构中 pH 不均匀性的机制、后果和调节：对癌症治疗的影响

• 批准号: G0700698/1
• 负责人: Pawel Swietach
• 金额: $ 41.26万
• 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: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0700698%2F1
• 关键词: Mechanisms; consequences; regulation; pH; non

Our aim is to study the mechanisms that regulate the acid/base balance (pH) in multi-cellular tissue, with particular emphasis on tumours.Living cells produce acid, an end-product of metabolism. Acid must be vented out of cells, to the nearest blood capillary, in order to maintain an intracellular pH (pHi) that is permissive for healthy cell function. Efficient venting of acid is also necessary to maintain uniform pHi across multi-cellular tissue. This is particularly critical for under-perfused and metabolically-active tissues, such as developing tumours, where variable cell-to-capillary diffusion distances predispose to pHi-gradients and core-acidity.Although significant progress has been made in the field of pHi-regulation in isolated cells, little is known about the integrated mechanisms that operate at tissue-level. Molecules likely to contribute to the latter include pH buffers, carbonic anhydrase enzymes, gap junction channels and acid/base membrane transporters. We will investigate these mechanisms using molecular biology, pH imaging and computational modelling. The research will use large, three-dimensional clusters (‘spheroids’) of cancer-derived cells as an in vitro model of developing tumours.The good survival prospects of cancer may suggest that efficient mechanisms for venting acid are implemented in tumours. Inhibiting these mechanisms may offer novel therapeutic strategies for treating cancer. Manipulation of pH within and outside cells may also affect the cellular uptake of certain weakly basic drugs that are currently used in chemotherapy.

我们的目标是研究调节多细胞组织中酸/碱平衡 (pH) 的机制，特别是肿瘤。活细胞产生酸，这是新陈代谢的最终产物。酸必须从细胞中排出，到达最近的毛细血管，以维持细胞内 pH (pHi)，以保证健康的细胞功能。有效排出酸对于维持多细胞组织的 pHi 均匀也是必要的。这对于灌注不足和代谢活跃的组织尤其重要，例如正在发育的肿瘤，其中不同的细胞到毛细血管的扩散距离容易产生 pHi 梯度和核心酸度。尽管在分离细胞的 pHi 调节领域已经取得了重大进展，但人们对在组织水平上运作的整合机制知之甚少。可能有助于后者的分子包括 pH 缓冲剂、碳酸酐酶、间隙连接通道和酸/碱膜转运蛋白。我们将利用分子生物学、pH 成像和计算模型来研究这些机制。该研究将使用癌症衍生细胞的大型三维簇（“球体”）作为肿瘤发展的体外模型。癌症良好的生存前景可能表明肿瘤中实施了有效的排酸机制。抑制这些机制可能为治疗癌症提供新的治疗策略。细胞内外 pH 值的控制也可能影响细胞对目前化疗中使用的某些弱碱性药物的摄取。