Investigations of the natural occurrence of hydroxyurea in animals

动物体内羟基脲自然存在的研究

• 批准号: RGPIN-2016-04406
• 负责人: Ballantyne, James
• 金额: $ 2.26万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683939
• 关键词: Investigations; natural; occurrence; hydroxyurea; animals

We have discovered an antibiotic compound, hydroxyurea is found in high levels in an elasmobranch (sharks skates and rays), the little skate, Leucoraja erinacea, and lower levels in many other animals including mammals. Hydroxyurea has antiviral, antibacterial and antineoplastic properties and has been, or is, used in the treatment of a variety of neoplastic diseases, sickle cell anemia, psoriasis, myeloproliferative diseases and infectious diseases such as HIV. It is listed as an “essential medicine” by the World Health Organization. Hydroxyurea was previously not thought to occur naturally in animals so this discovery has the potential to open new avenues of treatment in human medicine. We hypothesize hydroxyurea plays a role in the innate immune system of animals especially. The proposed research will establish the metabolic pathway(s) by which hydroxyurea is synthesized as well as how it is transported into or out of cells, its rate of turnover in the body and its mechanism of degradation. The skate will be used as the model for these studies since the highest levels recorded to date occur in this species. Hydroxyurea accumulates in a tissue-specific manner with some tissues having higher levels. This raises the questions of whether it is synthesized in each tissue or centrally and is transported to each tissue. An important aspect of these studies will be to establish how HU fits into the nitric oxide pathways since clinical studies indicate exogenously applied hydroxyurea increases nitric oxide levels. The methods include using liquid chromatography tandem mass spectrometry in tracer studies using 15N-labelled compounds to establish the precursors of hydroxyurea in several tissues of the skate. 15N-hydroxyurea will be used to determine the rate of turnover in the plasma and membrane transporter characteristics in isolated membrane vesicles from various tissues of the skate. 15N- and 13C-hydroxyurea will be used to determine the degradation pathways. Two Ph.D. students will be trained in these methods. These studies will provide the basis for future studies into ways to exploit this knowledge to benefit human medicine. The main outcomes of the proposed research will be an understanding of hydroxyurea metabolism and an improved understanding of the nitric oxide system in which it likely plays a role.

我们已经发现了一种抗生素化合物，在板鳃类（鲨鱼和鳐），小鳐，Leucoraja erinacea中发现了高水平的羟基脲，而在许多其他动物（包括哺乳动物）中含量较低。羟基脲具有抗病毒、抗菌和抗肿瘤特性，并且已经或正在用于治疗多种肿瘤性疾病、镰状细胞性贫血、牛皮癣、骨髓增生性疾病和感染性疾病如HIV。它被世界卫生组织列为“基本药物”。 此前人们认为，羟基脲在动物体内并不天然存在，因此这一发现有可能为人类医学开辟新的治疗途径。 我们推测羟基脲在动物的先天免疫系统中起着重要作用。拟议的研究将建立合成羟基脲的代谢途径，以及如何将其运入或运出细胞，其在体内的周转率及其降解机制。 旱冰鞋将被用作这些研究的模型，因为迄今为止记录的最高水平发生在这个物种中。羟基脲以组织特异性方式蓄积，某些组织的水平较高。这就提出了一个问题，即它是在每个组织中合成的，还是集中合成并转运到每个组织。这些研究的一个重要方面将是确定HU如何适应一氧化氮途径，因为临床研究表明外源性施用的羟基脲会增加一氧化氮水平。这些方法包括使用液相色谱串联质谱法在示踪剂研究中使用15 N-标记的化合物，以建立在几个组织的滑冰的羟基脲的前体。15 N-羟基脲将用于测定来自旱冰鱼各种组织的分离膜囊泡中的血浆周转率和膜转运蛋白特征。15 N-和13 C-羟基脲将用于确定降解途径。两个博士学生将接受这些方法的培训。这些研究将为未来研究如何利用这些知识造福人类医学提供基础。拟议研究的主要成果将是对羟基脲代谢的理解，以及对它可能发挥作用的一氧化氮系统的更好理解。