Iron Catalyzed H2S and its Prevalence in Hemolytic and Iron Overload Disorders

铁催化的 H2S 及其在溶血和铁过载疾病中的患病率

• 批准号: 10191027
• 负责人: CHRISTOPHER Michael HINE
• 金额: $ 32.2万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10191027
• 关键词: Address; Affect; Amino Acids; Anemia; Area; Binding; Binding Proteins; Biochemical; Biological; Biological Process; Blood; Blood Circulation; Blood Proteins; Blood Transfusion; Cardiovascular system; Catalysis; Cell Respiration; Cells; Chemicals; Chemistry; Chronic; Clinical; Cysteine; Cytolysis; Data; Development; Dietary Intervention; Disease; Disease Management; Dose; Drug Metabolic Detoxication; Elements; Equilibrium; Erythrocytes; Excision; Ferritin; Future; Gases; Generations; Glucosephosphate Dehydrogenase Deficiency; Health; Hematological Disease; Hematology; Heme; Hemochromatosis; Hemoglobin; Hemolysis; Hemolytic Anemia; Homeostasis; Hydrogen Sulfide; In Vitro; Inherited; Iron; Iron Overload; Kinetics; Life; Lipids; Lupus; Lytic; Maintenance; Mammals; Mass Spectrum Analysis; Measurement; Metals; Methodology; Modeling; Nature; Nucleic Acids; Organ; Outcome; Oxidation-Reduction; Oxygen; Pathologic; Pathology; Peripheral; Physiological; Physiology; Prevalence; Prevention; Production; Proteomics; Reaction; Reactive Oxygen Species; Research; Role; Sickle Cell; Sickle Cell Anemia; Signal Transduction; Specificity; Sulfur Amino Acids; Supplementation; Techniques; Testing; Thalassemia; Therapeutic; Tissue Extracts; Tissues; Transfusion; United States National Institutes of Health; Vitamin B6; Xenobiotics; base; chelation; chemical reaction; detection method; direct application; exposure route; haemoferritin; hypothalamic pituitary axis; improved; in vivo; innovation; metabolomics; mouse model; novel; nutritional approach; premature; prevent; protein degradation; targeted treatment

PROJECT SUMMARY/ABSTRACT Iron is an essential element required for redox reactions involved in cellular respiration, macromolecular synthesis, and xenobiotic detoxification. In mammals, its major role is in the production of red blood cells (RBCs) and transferring of oxygen throughout the body. Despite the life sustaining requirement of iron, its highly reactive nature to catalyze the production of damaging reactive oxygen and metabolite species (ROMS) necessitates mechanisms for its sequestration and harnessing of activity. This is primarily achieved through the binding of iron to heme, hemoglobin, and ferritin in RBCs and tissues. However, in hematological disorders such as sickle cell anemia, lytic crisis, and hemochromatosis, there is an increase in unbound iron release and overload. Increased ROMS by iron overload drive pathologies in cardiovascular tissues and other peripheral organs associated with these hematological disorders. Current clinical therapies targeting iron accumulation via metal chelation or blood removal/transfusions have been met with mixed results and come with clinical consequences. Thus, better characterizing and controlling iron catalyzed reactions in the blood remain as challenges as well as open avenues for treating iron-related hematological diseases. In this NIH New Directions in Hematological Research (SHINE-II) proposal, we address these issues via biochemical, metabolomic, proteomic, and nutritional approaches and innovations. We focus these methodologies on a chemical reaction my lab has recently uncovered in which hydrogen sulfide (H2S) gas is produced by an iron- and vitamin B6- coordinated catalysis of cysteine under physiological conditions. Much like iron, H2S serves beneficial and detrimental physiological roles throughout the body which are governed by dose, exposure route, and tissue specificity. The role of iron catalyzed H2S in prevention or promotion of hematological disorders is unknown. Here, we will test the hypothesis that iron catalyzed H2S in the blood is a modifiable factor in the initiation or progression of the blood disorders sickle cell anemia and hemochromatosis. To test this hypothesis, we will pursue one central AIM and determine the mechanism and capacities for H2S production catalyzed by iron in vitro and in blood derived from models of hemolytic anemia and iron-overload. To accomplish this aim, we will 1) Employ selective and sensitive H2S and sulfhydryl detecting techniques to explore the biochemical mechanisms, requirements, and downstream signaling of iron-catalyzed H2S in vitro and in blood and tissues ex vivo, and 2) Apply sulfur amino acid and vitamin B6 based dietary interventions as a means of preventing or slowing pathologies associated with sickle cell hemolytic crisis in vivo via modulating endogenous H2S production. Utilization of these approaches to investigate this novel chemistry will underscore the significance of iron catalyzed H2S production in the blood and the therapeutic potential of controlling it in hematological diseases.

项目概要/摘要 铁是参与细胞呼吸、大分子氧化还原反应所需的必需元素 合成和外源物解毒。在哺乳动物中，它的主要作用是产生红细胞 (RBC) 以及氧气在全身的输送。尽管铁是维持生命的必需品，但其高反应性 大自然催化破坏性活性氧和代谢物（ROMS）的产生是必要的 其活动的隔离和利用机制。这主要是通过绑定来实现的 铁在红细胞和组织中转化为血红素、血红蛋白和铁蛋白。然而，在血液系统疾病中，例如镰状细胞病 细胞贫血、溶解危象和血色素沉着症，未结合铁释放和超负荷增加。 铁超载导致的 ROMS 增加会导致心血管组织和其他外周器官出现病变 与这些血液系统疾病有关。当前针对通过金属积累铁的临床疗法 螯合或取血/输血的结果好坏参半，并带来临床后果。 因此，更好地表征和控制血液中铁催化的反应仍然是挑战和挑战 为治疗与铁相关的血液疾病开辟了途径。 NIH 血液学新方向 研究（SHINE-II）提案，我们通过生物化学、代谢组学、蛋白质组学和营养学来解决这些问题 方法和创新。我们将这些方法集中在我的实验室最近进行的化学反应上 发现其中硫化氢 (H2S) 气体是由铁和维生素 B6 协调催化产生的 生理条件下的半胱氨酸。与铁非常相似，H2S 具有有益和有害的生理作用 整个身体，由剂量、暴露途径和组织特异性控制。铁的作用 催化 H2S 在预防或促进血液疾病方面的作用尚不清楚。在这里，我们将测试 假设血液中铁催化的 H2S 是引发或进展的可改变因素 血液疾病镰状细胞性贫血和血色素沉着症。为了检验这一假设，我们将追求一个 中心目标并确定体外和体内铁催化产生 H2S 的机制和能力 来自溶血性贫血和铁超载模型的血液。为了实现这一目标，我们将 1) 雇用 选择性和灵敏的 H2S 和巯基检测技术来探索生化机制， 铁催化 H2S 体外以及离体血液和组织中的需求和下游信号传导，以及 2) 应用含硫氨基酸和维生素 B6 为主的饮食干预措施作为预防或减缓的手段 通过调节内源性 H2S 的产生来治疗与体内镰状细胞溶血危象相关的病理学。 利用这些方法来研究这种新颖的化学反应将强调铁的重要性 催化血液中 H2S 的产生以及控制它在血液疾病中的治疗潜力。

项目成果

H2S serves as the immunoregulatory essence of apoptotic cell death.

H2S是细胞凋亡的免疫调节本质。

• DOI: 10.1016/j.cmet.2023.12.006
• 发表时间: 2024
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Hine,Christopher;Ponti,AndrásK;Cáliz-Molina,MaríaÁngeles;Martín-Montalvo,Alejandro
• 通讯作者: Martín-Montalvo,Alejandro