Molecular characterization of biliverdin IXbeta reductase

胆绿素 IXbeta 还原酶的分子表征

• 批准号: 10580034
• 负责人: Wadie F Bahou
• 金额: $ 49.3万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580034
• 关键词: Address; Advanced Development; Affect; Aging; Anemia; Animal Model; Animals; Applications Grants; Applied Genetics; Basic Science; Bilirubin; Biliverdin reductase; Biliverdine; Biochemical; Biochemistry; Bioenergetics; Blood Cells; Blood Platelets; Buffers; Catabolism; Cell Aging; Cell Line; Cell model; Cells; Cellular Metabolic Process; Chemicals; Chemistry; Clinical; Collaborations; Computational Biology; Coupling; Cues; Cytoprotection; Data; Defect; Detection; Development; Disease; Enzymes; Equilibrium; Erythrocytes; Erythroid; Erythropoiesis; Evaluation; Funding; Future; Genetic; Genetic study; Goals; Grant; Health; Hematopathology; Hematopoiesis; Hematopoietic; Heme; Homologous Gene; Human; In Vitro; Inflammatory; Isomerism; Joints; Knock-out; Lead; Link; Lipid Peroxidation; Manuscripts; Megakaryocytes; Metabolic; Metabolic Pathway; Metabolism; Methodology; Modeling; Molecular; Mus; Neonatal; Oxidation-Reduction; Oxidoreductase; Oxygenases; Pathway interactions; Patients; Phenotype; Physiological; Platelet Count measurement; Population; Production; Proteins; Reaction; Reactive Oxygen Species; Reagent; Regulation; Research; Research Design; Role; Signal Transduction; Stress; Structural Models; Tetrapyrroles; Thrombopoiesis; Validation; Work; cellular targeting; chemotherapy; cohort; computer studies; design; drug development; experimental study; in vivo; in vivo Model; induced pluripotent stem cell; inhibitor; insight; mouse model; novel; oxidant stress; pharmacologic; pre-clinical; progenitor; public health relevance; stem cells; structural biology; translational study

Project Summary/Abstract Research proposed in this grant application builds on extensive genetic, biochemical and animal studies designed to further characterize and validate biliverdin IXβ reductase (BLVRB) as a novel cellular target regulating human platelet production in situations of stress hematopoiesis, with concomitant effects on erythroid development and repopulation. Although heme degradation is largely studied as a processing pathway designed to clear pro-oxidant (free) heme generated during cellular senescence (or metabolism), heme catabolic enzymes are also known to maintain function(s) in cellular signaling and cytoprotection, and tetrapyrrole byproducts biliverdin (BV) and bilirubin (BR) function in redox reactions as potent buffer(s) against oxidant stress. We now challenge existing dogma, hypothesizing that redox-regulated activity involving heme catabolism functions in a unique metabolic pathway controlling hematopoietic lineage fate with divergent effects on erythroid/megakaryocyte balance. Research goals are accomplished through two synergistic specific aims, designed to (1) delineate cellular mechanisms of BLVRB-regulated Mk/Erythroid redox coupling and cytoprotection in vitro, and (2) define and expand upon mechanisms of lineage-restricted speciation and cytoprotection in vivo, collectively designed to dissect Blvrb-regulated perturbed pathways controlling E/Meg lineage speciation from MEPs during stress hematopoiesis. Basic science implications are broadly relevant to (1) metabolic and bioenergetic consequences of hematopoiesis, (2) heme-regulated redox chemistry, and (3) novel cellular target validation. Clinical/translational implications are designed to enhance our understanding of mechanisms of disease pertaining to stem cell metabolism, aging, anemia and platelet production. Unique reagents and cell lines generated and characterized include (1) murine models of Blvrb- and Blvra-deficiency, (2) iPSC models with targeted BLVRB knock-outs, (3) biliverdin IXβ (and IXγ, IXδ) isomer detection and production methodologies. All proposed studies are formulated on pre-existing studies in subject cohorts, and proposed experiments are predicated on reagents and expertise currently available or in advanced development among the research team.

项目概要/摘要 本拨款申请中提出的研究建立在广泛的遗传、生化和动物研究的基础上 旨在进一步表征和验证胆绿素 IXβ 还原酶 (BLVRB) 作为新型细胞靶标 在应激造血情况下调节人类血小板的产生，并对 尽管血红素降解主要作为一种加工过程进行研究。 旨在清除细胞衰老（或代谢）过程中产生的促氧化剂（游离）血红素的途径， 还已知血红素分解代谢酶可维持细胞信号传导和细胞保护的功能，并且 四吡咯副产物胆绿素 (BV) 和胆红素 (BR) 在氧化还原反应中作为有效的缓冲剂发挥作用 我们现在挑战现有的教条，假设氧化还原调节的活动涉及血红素。 分解代谢在独特的代谢途径中发挥作用，以不同的方式控制造血谱系的命运 对红细胞/巨核细胞平衡的影响是通过两个协同作用来实现的。 具体目标，旨在 (1) 描绘 BLVRB 调节的 Mk/Erythroid 氧化还原耦合的细胞机制 和体外细胞保护，以及（2）定义并扩展谱系限制的物种形成机制和 体内细胞保护，共同设计用于剖析 Blvrb 调节的控制 E/Meg 的扰动途径 应激造血过程中 MEP 的谱系形成与基础科学意义广泛相关。 (1) 造血的代谢和生物能后果，(2) 血红素调节的氧化还原化学，以及 (3) 新颖的细胞靶标验证旨在增强我们的理解。 与干细胞代谢、衰老、贫血和血小板产生有关的疾病机制。 生成和表征的试剂和细胞系包括 (1) Blvrb 和 Blvra 缺陷的小鼠模型， (2) 具有靶向 BLVRB 敲除的 iPSC 模型，(3) 胆绿素 IXβ（和 IXγ、IXδ）异构体检测和 所有拟议的研究都是根据受试者队列中现有的研究制定的，并且 拟议的实验基于当前可用或先进的试剂和专业知识 研究团队之间的发展。