Sensing And Signalling Of Extracellular Ca2+ In The Islet Of Langerhans

朗格汉斯岛细胞外 Ca2 的传感和信号传导

• 批准号: EP/Y002830/1
• 负责人: Jiangbo Zhao
• 金额: $ 20.64万
• 依托单位: University of Hull
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY002830%2F1
• 关键词: Sensing; Signalling; Extracellular; Ca2+; Islet

This project aims to develop a new sensing platform to resolve a long-standing puzzle: how extracellular Ca2+ coordinates pancreatic islet beta-cells for pulsatile insulin secretion. The latter is key to maintain the blood glucose homeostasis.Free ionic Ca2+ is now recognised as an indispensable messenger in mediating cellular activities in nearly every aspect of cellular life for almost all mammalian cells. Although the roles of intracellular Ca2+ in relation to different biological functions have been well characterised, insights into extracellular Ca2+ are constrained by the lack of appropriate sensing methodology capable of distinguishing the subtle changes of Ca2+ over the high basal level (e.g., micromolar scale variances in millimolar order baseline). For one sensor mainstream - fluorescent indicators, they are particularly limited by the background autofluorescence (due to the use of a shorter wavelength excitation, indicators themselves fluoresce with longer wavelength emissions even in the absence of ions of interest). To overcome this limit, the proposed research will introduce state-of-the-art upconversion luminescence, which features the capacity of converting 980 nm infrared light excitation into visible emissions, to combine with conventional fluorescent indicators. Such a hybrid sensor will represent the world-first one that enables characterising extracellular Ca2+ quantitatively.The upconversion-synergised hybrid sensor will then be applied to address how extracellular Ca2+ participates in coordinating pulsatile insulin secretion from pancreatic islet beta-cells - a key metabolic process coupled to glucose metabolism. The advent of such a sensor, in conjunction with a bespoke microfluidic device, will provide an opportunity to quantify the link between extracellular Ca2+ and pulsatile insulin secretion in isolated islets from mice at different metabolic states (health, prediabetes and type 2 diabetes). These analyses will lead to fundamental knowledge gains which can improve the current understanding on the pathophysiology of type 2 diabetes and may suggest new therapeutic strategies for the management of this major chronic disorder, thereby benefiting people living with type 2 diabetes (in 2021, 4.9 million in the UK and 536.6 million worldwide).

该项目旨在开发一种新的传感平台，以解决一个长期存在的难题：细胞外Ca 2+如何协调胰岛β细胞进行脉动胰岛素分泌。后者是维持血糖稳态的关键。游离离子Ca 2+现在被认为是几乎所有哺乳动物细胞在细胞生命的几乎各个方面介导细胞活动的不可或缺的信使。虽然细胞内Ca 2+与不同生物学功能相关的作用已经得到很好的表征，但对细胞外Ca 2+的了解受到缺乏能够区分Ca 2+在高基础水平上的细微变化的适当传感方法的限制（例如，微摩尔尺度的变化，以毫摩尔级基线计）。对于一种传感器主流-荧光指示剂，它们特别受到背景自发荧光的限制（由于使用较短波长的激发，即使在不存在感兴趣的离子的情况下，指示剂本身也会发出较长波长的荧光）。为了克服这一限制，拟议的研究将引入最先进的上转换发光，其特点是将980 nm红外光激发转换为可见光发射的能力，与传统的荧光指示剂联合收割机相结合。这种混合传感器将代表世界上第一个能够定量表征细胞外Ca 2+的传感器。然后，上转换协同混合传感器将被应用于解决细胞外Ca 2+如何参与协调胰岛β细胞的脉动胰岛素分泌-这是与葡萄糖代谢耦合的关键代谢过程。这种传感器的出现，结合定制的微流体装置，将提供一个机会来量化细胞外Ca 2+和脉动胰岛素分泌之间的联系，在不同的代谢状态（健康，前驱糖尿病和2型糖尿病）的小鼠分离的胰岛。这些分析将带来基础知识的收获，可以提高目前对2型糖尿病病理生理学的理解，并可能为这种主要慢性疾病的管理提出新的治疗策略，从而使2型糖尿病患者受益（2021年，英国有490万人，全球有5.366亿人）。