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“有毒金属和类金属”(从现在起将缩写为“有毒金属”)。 或超过全球自然排放量，预计还会增加。虽然 过去已经采取了严格的措施，以尽量减少人类对 由于人类对有毒金属的依赖，相当数量的这些毒素持续存在 并因此继续进入食物链。因此，数百万人 的人，包括儿童，都暴露在这些持久性污染物中 从它们在普通人群中的血液浓度来证明。然而，对这些浓度的解释提出了一个主要问题，因为功能生化联系 暴露于这些无机污染物和它们可能与特定污染物的联系 人类疾病(如自闭症)在很大程度上是未知的。在这方面， 血流代表了一个关键的生物部位，毒物学上 高度相关的基于生物无机化学的相互作用正在展开。虽然这些过程共同决定了靶器官(如肾脏)的损害，但人们对它们的了解还不够清楚。这种不好的情况必须归因于有毒物质的低浓度 涉及的金属和分析全血的一般困难，全血由红细胞和血浆组成。 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 与毒理相关的砷、镉、 血液中的汞和/或铅物种。由于将采用的分析方法允许直接分析生物体液(如血浆、红细胞胞浆)中的必需和有毒金属物种，拟议的方法注定将为后者的哺乳动物毒理学提供全新的见解。长期目标将集中在更好地了解血浆、红细胞胞浆、全血、靶器官和整个动物中持久性有毒金属的生物化学。我们尤其会： A)探测有毒金属与血浆蛋白和血浆中人体血液代谢物的动态相互作用 B)确定红细胞胞浆中有毒金属的新靶蛋白 C)确定新的有毒金属代谢物的结构特征 是在全血中形成的 D)确定实际有毒金属种类或代谢物 在血液中形成并转移到毒物靶器官和 E)观察有毒金属物种引起的全身性扰动 全动物(新西兰大白兔)的血浆金属蛋白质组，定义为含有结合铜、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持久性有毒金属的长期暴露。