Probing bioinorganic chemistry processes in the bloodstream

探索血液中的生物无机化学过程

• 批准号: RGPIN-2019-04376
• 负责人: Gailer, Juergen
• 金额: $ 2.4万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=713910
• 关键词: Probing; bioinorganic; chemistry; processes; bloodstream

Human activities today emit quantities of 'toxic metals and metalloids' (this phrase will be shortened to 'toxic metals' from now on) into the environment that rival or exceed natural global emissions and they are projected to increase. Although stringent measures have been put into place in the past to minimize the exposure of human populations to toxic metals, considerable levels of these toxins persist in soils and thus continue to enter the food chain. Consequently, millions of people including children are exposed to these persistent pollutants as is evidenced by their blood concentrations in the general population. The interpretation of these concentrations, however, poses a major problem because the functional biochemical connections between the exposure to these inorganic pollutants and their possible link to specific human diseases (e.g. autism) are largely unknown. In this context, the bloodstream represents a critical biological site where toxicologically highly relevant bioinorganic chemistry-based interactions unfold. Although these processes collectively determine the damage of target organs (e.g. the kidneys), they are not well understood. This undesirable situation must be attributed to the low concentrations of the toxic metals involved and the general difficulty of analyzing whole blood, which is comprised of red blood cells and blood plasma. My research program will involve the application of highly appropriate advanced research tools to probe the biochemistry of toxicologically relevant arsenic, cadmium, mercury and/or lead species in the bloodstream. Since the analytical methodology that will be employed allows to directly analyze biological fluids (e.g. blood plasma, red blood cell cytosol) for essential and toxic metal species, the proposed approach is destined to provide fundamentally new insight into the mammalian toxicology of the latter. The long-term goals will focus on better understanding the biochemistry of persistent toxic metals in plasma, red blood cell cytosol, whole blood, target organs and whole animals. In particular, we will: a) probe dynamic interactions of toxic metals with plasma proteins and human blood metabolites in plasma b) identify novel target proteins of toxic metals in red blood cell cytosol c) structurally characterize novel toxic metal metabolites that are formed in whole blood d) identify the actual toxic metal species or metabolites that are formed in the bloodstream and translocated to toxicological target organs and e) observe toxic metal species-induced systemic perturbations of the plasma metalloproteome, defined as all proteins that contain bound copper, iron, zinc, cobalt, manganese and selenium, in whole animals (New Zealand white rabbits). The new insight that will be gained from these studies will contribute to develop policies that better protect humans from the chronic exposure to persistent toxic metals.

今天的人类活动向环境中排放了大量的“有毒金属和准金属”（从现在开始，该短语将缩写为“有毒金属”） 或超过全球自然排放量，并且预计还会增加。虽然 过去已经采取了严格的措施来尽量减少人类的暴露 有毒金属的人群，这些毒素的水平相当高 土壤，从而继续进入食物链。因此，数百万 包括儿童在内的人暴露于这些持久性污染物 一般人群的血液浓度就证明了这一点。然而，对这些浓度的解释提出了一个主要问题，因为功能性生化联系 接触这些无机污染物及其与特定物质的可能联系之间 人类疾病（例如自闭症）在很大程度上是未知的。在此背景下， 血液是一个重要的生物部位，毒理学上 高度相关的基于生物无机化学的相互作用展开。尽管这些过程共同决定了靶器官（例如肾脏）的损伤，但人们对它们的了解还不够深入。这种不良情况一定是由于有毒物质浓度低造成的。 涉及的金属以及分析由红细胞和血浆组成的全血的一般困难。 我的 研究计划将涉及应用高度合适的先进研究工具来探索 毒理学相关的砷、镉的生物化学， 血液中的汞和/或铅物质。由于将采用的分析方法允许直接分析生物液体（例如血浆、红细胞胞质溶胶）中的必需金属和有毒金属物质，因此所提出的方法注定将为后者的哺乳动物毒理学提供全新的见解。长期目标将侧重于更好地了解血浆、红细胞胞质、全血、靶器官和整个动物中持久性有毒金属的生物化学。特别是，我们将： a) 探测血浆中有毒金属与血浆蛋白和人体血液代谢物的动态相互作用 b) 识别红细胞胞质中有毒金属的新靶蛋白 c) 新型有毒金属代谢物的结构表征 全血中形成的 d) 识别实际的有毒金属种类或代谢物 在血液中形成并转运至毒理学靶器官 e) 观察有毒金属物质引起的系统扰动 血浆金属蛋白质组，定义为整个动物（新西兰白兔）中含有结合铜、铁、锌、钴、锰和硒的所有蛋白质。 从这些研究中获得的新见解将有助于制定政策，更好地保护人类免受长期接触持久性有毒金属的影响。