Regulation of heme oxygenase-1 by biliverdin reductase

胆绿素还原酶对血红素加氧酶-1 的调节

基本信息

批准号：
7319814
负责人：
Mahin D. Maines
金额：
$ 34.65万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-15 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7319814
关键词：
Address Affect Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Antioxidants Apoptotic Bilirubin Biliverdin reductase Biliverdine Binding Binding Sites Biological Blood Circulation Blood Urea Nitrogen Blood urea nitrogen measurement Catalysis Cell Differentiation process Cell Line Cell Nucleus Cell physiology Cells Chemicals Co-Immunoprecipitations Complex Condition Containment Creatinine Cultured Cells Cyclic AMP Cytoplasm Cytoprotection Cytosol DNA DNA Binding Data Defense Mechanisms Dimerization Disease Docking Dominant-Negative Mutation Doxycycline Elements Enhancers Enzymes Erythrocytes Event Exposure to FOS gene Family Family member Free Radicals Functional disorder Funding Gel Gelshift Analysis Gene Expression Genes Genetic Transcription Growth Factor Receptors Half-Life Health Heme Hemeproteins Hemoglobin Hemolysis Human In Vitro Individual Inflammation Inherited Injury Insulin Receptor Investigation Iron Isomerism JUN gene Kidney Kidney Failure Link Liver MAP Kinase Gene Malignant neoplasm of kidney Mediating Mediator of activation protein Membrane Molecular Monitor Morphology Mus Nuclear Nuclear Translocation Numbers One-Step dentin bonding system Operative Surgical Procedures Organ Organ Transplantation Oxidation-Reduction Oxidative Stress Oxidoreductase Oxygenases Pathway interactions Pharmaceutical Preparations Phenylhydrazines Phosphopeptides Phosphorylation Phosphorylation Site Phosphotransferases Physiology Plasmids Process Protein Binding Protein Kinase Protein-Serine-Threonine Kinases Proteins Rate Rattus Reactive Oxygen Species Regulation Regulatory Element Renal carcinoma Renal function Renal tubule structure Reperfusion Injury Research Response Elements Role Series Serine Serum Signal Pathway Signal Transduction Site Site-Directed Mutagenesis Small Interfering RNA Source Specificity Stimulus Stress Structure Testing Tetrapyrroles Threonine Tissues Toxic effect Toxicology Transcription Factor AP-1 Transgenic Organisms Translating Tyrosine Vasodilation Vasodilation disorder Yeasts activating transcription factor angiogenesis bZIP Domain base biological adaptation to stress catalyst dimer environmental agent free radical oxygen heme oxygenase-1 heme oxygenase-2 in vivo inhibitor/antagonist insight kidney cell member mouse model novel therapeutics nucleocytoplasmic transport oxidation phenylhydrazine promoter protein degradation protein protein interaction protoporphyrin IX research study response trafficking transcription factor transgene expression yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): The heme moiety of denatured hemoproteins (heme-proteins) is degraded by HO-1 & HO-2, to CO and biliverdin (BV), an HO activity inhibitor; BV is reduced by its reductase (BVR) to the antioxidant, bilirubin. CO has anti-inflammatory and vasodilatory activities. Stimuli that cause oxidative stress and hemoprotein denaturation, such as surgical interventions, inherited and transmitted hemolytic diseases, and certain drugs, industrial and environmental agents, induce ho-1. The kidney tubules are the target of potent pro-oxidant activity of heme-compounds. To date, no effective strategy has been described to counter heme-protein renal toxicity; however, increase in HO-1 activity by activation of stress-activated response elements, e.g., AP-1/CRE, AREs (antioxidant response elements) is considered cytoprotective. The activation involves cell-line independent binding of basic leucine zipper (bZip) transcription factors: c-Jun, ATF- 2/CREB, and Nrf2. The MAPK and PI3-K pathways transduce signals for activation of bZip factors and "cross talk" using PKCs. bZip factor activity is subject to the identity of its dimeric partner. Phosphorylation of the ultimate target gene product, e.g., HO-1, alters its activity and turnover. In vitro and in cultured cells, we have discovered that: the human (h) BVR is one of the rare kinases that control MAPK and PI3-K signaling; is a bZip factor; activated by ho-1 inducers; and, traffics between the cytosol and nucleus. hBVR binds to AP-l/CRE and ARE elements and also enhances ATF-2 and Nrf2 binding to AP-1 and/or ARE; promotes induction and activation of ATF-2, c-Jun and c-Fos; activates kinase mediators of ho-1 response, i.e. PKCs and PKB/Akt; and, causes cell differentiation. BVR regulates ho-1 oxidative stress response and its anti-apoptotic effect. The overall objective of this application is to further investigate regulation of HO-1 activity by BVR at the molecular and cellular levels and to extend the investigation to the intact animal. Specific aims are to examine: i) function of BVR as kinase:kinase in phosphorylation, activity, and turnover of HO-1; 2) the role of hBVR in transcriptional activity of ATF-2 and Nrf2; and, 3) whether increased levels of BVR protect against heme-mediated injury. Mice expressing hBVR in renal tubules and treated with the hemolytic agent, phenylhydrazine, will be analyzed for pathophysiology, antioxidant status, kinase activities and HO-1 levels. Liver will serve as the non-target organ as control for the expression of the transgene.

描述（由申请人提供）：变性血蛋白（血红素蛋白）的血红素部分被HO-1和HO-2降解为HO活性抑制剂CO和Biliverdin（BV）； BV通过其还原酶（BVR）降低为抗氧化剂胆红素。 CO具有抗炎和血管舒张活性。引起氧化应激和血蛋白变性的刺激，例如手术干预，遗传和传播溶血疾病，以及某些药物，工业和环境剂，诱导HO-1。肾小管是血红素化合物有效促氧化活性的靶标。迄今为止，尚未描述有效的策略来抵抗血红素蛋白肾毒性。但是，通过激活应力激活响应元件，例如AP-1/CRE，ARES（抗氧化反应元件），HO-1活性增加被认为是细胞保护的。激活涉及基本亮氨酸拉链（BZIP）转录因子的细胞系独立结合：C-JUN，ATF-2/CREB和NRF2。 MAPK和PI3-K途径使用PKCS激活BZIP因子和“交叉谈话”传导信号。 BZIP因子活动受其二聚体伴侣的身份约束。最终靶基因产物（例如HO-1）的磷酸化改变了其活性和周转率。在体外和培养的细胞中，我们发现：人（H）BVR是控制MAPK和PI3-K信号传导的稀有激酶之一；是BZIP因素；被HO-1诱导剂激活；以及细胞质和核之间的运输。 HBVR与AP-L/CRE结合，是元素，还增强了与AP-1和/或IS的ATF-2和NRF2结合；促进ATF-2，C-JUN和C-FOS的诱导和激活；激活HO-1反应的激酶介质，即PKC和PKB/AKT；并导致细胞分化。 BVR调节HO-1氧化应激反应及其抗凋亡作用。该应用的总体目的是进一步研究BVR在分子和细胞水平上对HO-1活性的调节，并将研究扩展到完整的动物。具体目的是检查：i）BVR作为激酶的功能：激酶在HO-1的磷酸化，活性和周转中的功能； 2）HBVR在ATF-2和NRF2转录活性中的作用； 3）BVR是否可以防止血红素介导的损伤升高。将在肾小管中表达HBVR并用溶血剂苯基羟嗪处理的小鼠进行病理生理学，抗氧化剂状态，激酶活性和HO-1水平进行分析。肝脏将用作非目标器官，作为转基因表达的控制。