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Molecular characterization of biliverdin IXbeta reductase

胆绿素 IXbeta 还原酶的分子表征

基本信息

批准号：
10210076
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
项目类别：
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/10210076
关键词：
Active Sites Address Advanced Development Affect Aging Anemia Animal Model Animals Applications Grants Applied Genetics Basic Science Bilirubin Biliverdin reductase Biliverdine Biochemical Biochemical Genetics Bioenergetics Blood Cells Blood Platelets Buffers C10 Catabolism Cell Aging Cell Line Cell model Cells Cellular Metabolic Process Chemicals Chemistry Clinical Clinical Data Complex Computational Biology Coupling Cues Cytoprotection Defect Degradation Pathway 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 NADP Names Neonatal Oxidation-Reduction Oxidoreductase Oxygenases Pathway interactions Patients Pharmacology Phenotype Physiological Platelet Count measurement Positioning Attribute Production Propionates Proteins Reaction Reactive Oxygen Species Reagent Regulation Research Research Design Role Signal Transduction Stress Structural Biochemistry Structural Models Structure Tetrapyrroles Thrombopoiesis Validation Work base cellular targeting chemotherapy cohort computer studies design drug development experimental study in vivo in vivo Model induced pluripotent stem cell inhibitor/antagonist insight mouse model novel oxidant stress pre-clinical preference progenitor public health relevance stem cells structural biology translational study

项目摘要

Name of Applicant (Last, First, Middle): BAHOU, Wadie F. Project Summary/Abstract Research proposed in this grant application builds on extensive genetic, biochemical and animal studies designed to further characterize and validate biliverdin IX 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 IX (and IX, IX) 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. PHS 416-9 (Rev. 6/09) Page Continuation Format Page

申请人姓名（最后、第一、中）：BAHOU, Wadie F。