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Bilateral BBSRC-FAPESP: A "speciomic" toolkit to investigate fatty acid-mediated changes in plasma zinc speciation and their physiological effects

双边 BBSRC-FAPESP：用于研究脂肪酸介导的血浆锌形态变化及其生理效应的“特异性”工具包

基本信息

批准号：
BB/V014684/1
负责人：
Alan Stewart
金额：
$ 99.78万
依托单位：
University of St Andrews
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FV014684%2F1
关键词：
Bilateral BBSRC FAPESP speciomic toolkit

项目摘要

There are 25 chemical elements that are required for mammalian life; 15 of these elements are metals. Zinc, in its ionised form Zn2+, is an essential metal ion in mammals and performs a wide range of important physiological functions by allowing many vital chemical reactions to occur. Zinc plays essential roles in fertility and development, the immune system, ageing, and major diseases such as diabetes, Alzheimer's disease and cancer. The mechanisms that deliver zinc to where it is needed following uptake from the diet and into the bloodstream, are only partially understood. It is known that the protein serum albumin, highly abundant in the blood, plays a vital role in transporting zinc (and other metals including calcium and magnesium) throughout the body. Albumin not only carries zinc through the circulatory system but also mediates its uptake into cells. Factors that control the interaction between zinc and albumin and its uptake into cells are not well studied, but are important to appreciate and influence their impact on health and disease. Albumin also transports other types of molecules (e.g. fatty acids, hormones), and binding of one molecule can affect binding of another at a separate site. For example, we previously identified that the primary zinc binding site is perturbed by fatty acid-binding elsewhere on the molecule. Physiological events that alter the composition of blood can therefore alter metal transport processes and the ability of albumin to sequester zinc. Such events may be short-term (e.g. fasting, eating, infection, stroke) or long-term (obesity, disease). Long-term alterations in blood chemistry are particularly likely to have serious consequences due to the knock-on effects caused by altered metal binding to various other molecules and delivery to cells. Indeed, we have shown that fatty acid-induced effects on zinc-binding to serum albumin result in other blood proteins, such as those involved in blood clotting, binding more zinc. In addition, we have found that cells take up zinc faster when they are cultured in the presence of fatty acids, which is a consequence of zinc interacting more with the proteins that promote its uptake into cells. Fatty acid levels in the blood are elevated in disease states, including obesity, type 2 diabetes and fatty liver disease - disorders associated with aberrant insulin signalling (insulin is the hormone responsible for regulating blood sugar levels) and increased tendency to develop blood clots. The fact that both processes are also zinc-dependent has led us to hypothesise that elevated fatty acid levels, particularly in disease states, impair plasma zinc handling and thus negatively affect these processes. As such our specific objectives are to:(1) Characterise the zinc-binding properties of human serum albumin in the presence of fatty acid mixtures found in normal and disease-related conditions.(2) Identify and characterise which plasma proteins zinc binds to in the presence of normal and disease-associated concentrations of fatty acids, whilst developing and exploiting new methods to enable such investigations.(3) Establish whether and how elevated plasma fatty acid levels influence insulin activation.(4) Examine the effect of fatty acid-albumin interactions on zinc movement and the proteins it binds to in the cells which line the blood vessels.(5) Determine how fatty acids influence insulin actions in primary endothelial cells via the albumin-zinc link.To achieve this, we will adopt an integrated approach that includes the use of a variety of methods to probe zinc-protein interactions, state-of-the-art and brand new approaches to investigate which proteins bind zinc, cellular studies to examine zinc movement in primary endothelial cells, in addition to molecular and functional tests to monitor insulin signalling. This work brings together the respective expertise of an interdisciplinary UK-Brazil team best placed to meet these challenges.

哺乳动物的生命需要25种化学元素；其中15种元素是金属。锌，以Zn2+的电离形式，是哺乳动物必不可少的金属离子，通过允许许多重要的化学反应发生，发挥着广泛的重要生理功能。锌在生育和发育、免疫系统、衰老以及糖尿病、阿尔茨海默病和癌症等重大疾病中起着至关重要的作用。从饮食中摄取锌并将其输送到需要的地方并进入血液的机制，目前还只是部分了解。众所周知，血清白蛋白在血液中含量很高，在全身运输锌（以及其他金属，包括钙和镁）方面起着至关重要的作用。白蛋白不仅通过循环系统携带锌，而且还介导其进入细胞。控制锌和白蛋白之间相互作用及其进入细胞的因素尚未得到很好的研究，但对了解和影响其对健康和疾病的影响很重要。白蛋白也运输其他类型的分子（如脂肪酸、激素），一个分子的结合可以影响另一个分子在不同位点的结合。例如，我们先前发现，初级锌结合位点受到分子上其他地方的脂肪酸结合的干扰。因此，改变血液成分的生理事件可以改变金属运输过程和白蛋白隔离锌的能力。这些事件可能是短期的（如禁食、进食、感染、中风），也可能是长期的（肥胖、疾病）。血液化学的长期改变尤其可能产生严重的后果，因为金属与各种其他分子结合并向细胞输送的改变会引起连锁反应。事实上，我们已经证明，脂肪酸诱导的锌与血清白蛋白结合的影响导致其他血液蛋白，如参与血液凝固的蛋白，结合更多的锌。此外，我们发现，当细胞在脂肪酸的存在下培养时，它们吸收锌的速度更快，这是锌与促进其进入细胞的蛋白质更多地相互作用的结果。在疾病状态下，血液中的脂肪酸水平升高，包括肥胖、2型糖尿病和脂肪肝疾病——与异常胰岛素信号（胰岛素是负责调节血糖水平的激素）相关的疾病，以及形成血栓的趋势增加。事实上，这两个过程也依赖于锌，这使我们假设脂肪酸水平升高，特别是在疾病状态下，损害血浆锌处理，从而对这些过程产生负面影响。因此，我们的具体目标是：(1)在正常和疾病相关条件下发现的脂肪酸混合物存在下，表征人血清白蛋白的锌结合特性。(2)在正常和疾病相关的脂肪酸浓度存在的情况下，确定和表征锌与哪些血浆蛋白结合，同时开发和利用新的方法来进行此类调查。(3)确定血浆脂肪酸水平升高是否以及如何影响胰岛素激活。(4)检查脂肪酸-白蛋白相互作用对锌运动的影响及其在血管细胞中结合的蛋白质。(5)确定脂肪酸如何通过白蛋白-锌连接影响胰岛素在原代内皮细胞中的作用。为了实现这一目标，我们将采用一种综合的方法，包括使用各种方法来探测锌-蛋白质的相互作用，最先进的和全新的方法来研究哪些蛋白质结合锌，细胞研究来检查锌在原代内皮细胞中的运动，以及分子和功能测试来监测胰岛素信号。这项工作汇集了一个跨学科的英国-巴西团队各自的专业知识，最适合应对这些挑战。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Albumin-mediated extracellular zinc speciation drives cellular zinc uptake.

DOI：
10.1039/d2cc02278h
发表时间：
2022-06-30
期刊：
CHEMICAL COMMUNICATIONS
影响因子：
4.9
作者：
Coverdale, James P. C.;van den Berg, Hugo A.;Khazaipoul, Siavash;Bridgewater, Hannah E.;Stewart, Alan J.;Blindauer, Claudia A.
通讯作者：
Blindauer, Claudia A.

Probing Zn

探测锌