Metabolomic phenotyping ("Metabolomics")

总而言之，根据我们之前发表的工作以及提出的新研究，我们预计这一科学核心将与HMS/UC氰化物反措施发现和开发中心的每个项目高度互动。代谢组学平台的主要目标将是沿着治疗开发途径进展化合物，初步研究已经强调了如何 我们已经实施的技术可以提供额外的科学价值。 具体的互动将包括： 项目一：该项目作为发现引擎，将产生大量未经精炼的化学“命中”。 确定哪些命中值得进一步优化将由代谢组学核心促进。代谢图谱将帮助我们确定化合物改善氰化物毒性的不同模式。这一信息确保了一组不同的分子和机制出现在以下对策中 我们保持在我们的管道中。沿着多个不同途径进行干预的能力可能会提供协同治疗结果。此外，我们还将评估在离散的脆弱状态下对氰化物的代谢反应，目的是精炼对氰化物暴露的敏感性或抵抗力的途径。这一努力可能会为这种脆弱的凝视产生候选生物标记物。 项目2：该项目是发现和哺乳动物功效测试之间的桥梁。正如在项目1中一样，对这些优化化合物的优先排序将受益于对其代谢作用的更准确了解。此外，核心将使我们能够评估正在研究的化合物的初始DMPK属性。 项目3：这个项目代表了我们将提名用于人工干预的化合物的最终评估。与前两个项目一样，该平台将提供对行动机制(S)的洞察，但在这种情况下，我们将转移到哺乳动物物种。此外，由于该平台对药物扰动很敏感，对哺乳动物物种的对策研究可能有助于我们判断它们的相对安全性和潜在的脱靶效应。 在我们的干预研究中嵌入了明确的机会，以确定氰化物中毒本身和有效救援的新诊断标记物。最后，对氰化物毒性继发的代谢紊乱的更广泛的了解可能会突出特定的酶，这些酶可能是治疗靶点或代谢物，本身可能被用作治疗干预措施。

In summary, based on our prior published work as well as the new studies presented, we anticipate that this Scientific Core will be highly interactive with each of the projects in the HMS/UC Center for Cyanide Countermeasure Discovery and Development. The main goal of the metabolomics platform will be to progress compounds along the therapeutic development pathway, preliminary studies already highlight how the technologies we have implemented can provide additional scientific value. Specific interactions will include: Project 1: This project serves as the discovery engine that will generate numerous unrefined chemical "hits." Identifying which hits merit further optimization will be facilitated by the metabolomics core. Metabolic profiling will help us identify distinct patterns by which compounds ameliorate cyanide's toxicities. This information ensures that a diverse group of molecules and mechanisms are represented among the countermeasures that we maintain in our pipeline. The ability to intervene along multiple distinct pathways will likely provide synergistic therapeutic outcomes. In addition, we will also assess the metabolic responses to cyanide in discrete vulnerable states, with the goal of refining the pathways responsible for sensitivity or resistance to cyanide exposure. This effort may generate candidate biomarkers for such vulnerable stares. Project 2: This project serves as a bridge between discovery and mammalian efficacy testing. As in Project 1, prioritization of these optimized compounds will benefit from a more precise understanding of their metabolic roles. In addition, the Core will allow us to assess initial DMPK attributes of compounds under study. Project 3: This project represents the final evaluation of compounds that we will nominate for human intervention. As in the first two projects, the platform will provide insight into mechanism(s) of action, but in this case as we move to mammalian species. Furthermore, because the platform is sensitive to pharmacological perturbations, studies of countermeasures in mammalian species may help us judge their relative safety and potential off-target effects. Embedded within our studies of interventions are clear opportunities to identify new diagnostic markers both of cyanide intoxication itself as well as effective rescue. Finally, a more complete understanding of the broad spectrum of metabolic derangements secondary to cyanide toxicity may highlight specific enzymes that might be therapeutic targets or metabolites that themselves may be used as therapeutic interventions.