Dynamic Regulation of Erythropoietin Gene Expression in Mammals

哺乳动物促红细胞生成素基因表达的动态调控

• 批准号: 8442054
• 负责人: Joseph Anthony Garcia
• 金额: --
• 依托单位: VA NORTH TEXAS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442054
• 关键词: Acetate-CoA Ligase; Acetates; Acetyl Coenzyme A; Acetylation; Acetyltransferase; Acute; Adult; Adverse event; Affect; Anemia; Area; Biochemical; Bioinformatics; Bolus Infusion; Cells; Chronic; Communities; Complex; Critical Care; Data; Deacetylase; Deacetylation; Development; Disease; EP300 gene; Endocrine; Ensure; Erythropoietin; Family; Funding; Gene Expression; Gene Targeting; Generations; Goals; Growth; Healthcare; Homeostasis; Hypoxia; Hypoxia Inducible Factor; Individual; Kidney; Link; Lipids; Liver; Malignant Neoplasms; Mammals; Mediating; Mediator of activation protein; Metabolism; Molecular; Molecular Target; Morbidity - disease rate; Mus; Nature; Outcome; Oxygen; Patients; Physiological; Pilot Projects; Play; Post-Translational Protein Processing; Process; Production; Proteins; Publishing; Regulation; Replacement Therapy; Reporting; Repression; Research Personnel; Risk; Risk Factors; Role; Science; Services; Signal Pathway; Signal Transduction; Stress; Testing; Transcription Coactivator; Veterans; bHLH-PAS factor HLF; base; hypoxia inducible factor 1; improved; in vivo; insight; member; mortality; novel; prevent; public health relevance; response; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Anemia, a common condition in Veteran patients, is a potent risk factor for increased morbidity and mortality when accompanying other disease states. Although therapies for anemia have improved over the past several decades, almost all current therapies involve bolus administration of erythropoietin (epo), an endocrine factor produced in the adult kidney and also in the liver with severe anemia. Non-physiological, bolus epo administration has untoward effects, including a possible increased thrombotic risk as well as an undesirable stimulatory effect on cancer. Understanding how epo is regulated will allow investigators to develop rational therapies besides epo replacement. Our current focus is defining molecular mechanisms regulating epo expression in mammals. Hypoxia Inducible Factor (HIF) transcription factors are a family of molecular mediators that induce the protective cellular response to hypoxia. We were the first to establish that the second HIF member, HIF-2¿, is critical for in vivo epo gene expression. While an essential role of HIF-2¿ in epo regulation is now recognized, the factors responsible for temporal epo gene expression in vivo, or for abnormal repression of epo gene expression in anemia patients, remain poorly understood. We recently identified a novel mechanism of HIF-2 signaling that affects epo regulation. Activity of HIF-1¿, the founding HIF member, is controlled predominantly by changes in protein levels, which is mediated by oxygen-dependent post-translational modifications of the HIF-1¿ protein. However, although the HIF-2¿ protein undergoes the same oxygen-dependent post-translational modifications, this mechanism is not the sole or even major mechanism for controlling HIF-2 signaling. If not the lack of oxygen, what then is the molecular trigger for activating HIF-2¿? Our central hypothesis is that hypoxia triggers changes in intermediary metabolism to effect acetylation of HIF-2¿. In Preliminary Data, we show that HIF-2¿ activity is controlled by two post-translational modifications, acetylation and deacetylation. In Pilot Studies, we identify the molecular and biochemical basis for HIF-2¿ acetylation, termed the acetate switch, which involves changes in intermediary metabolism to induce HIF-2¿ acetylation and coactivator recruitment. Deciphering how the acetate switch regulates HIF-2 signaling will provide novel insights into normal epo regulation and will identify selective molecular targets for modulation of endogenous epo gene expression in patients with anemia.

描述（由申请人提供）： 贫血是退伍军人患者的常见状况，是涉及其他疾病状态时发病率和死亡率增加的潜在危险因素。尽管在过去的几十年中，贫血的疗法有所改善，但几乎所有当前的疗法都涉及促进促红细胞生成素（EPO），这是成年肾脏中产生的内分泌因子，也是严重贫血的肝脏中产生的。非生理学的注释EPO给药具有不良影响，包括可能增加的血栓形成风险以及对癌症的不良刺激作用。了解如何调节EPO将允许研究人员除EPO替代外开发合理疗法。我们目前的重点是定义分子机制调节了哺乳动物的EPO表达。低氧诱导因子（HIF）转录因子是诱导细胞对低氧反应的分子介质家族。我们是第一个确定第二个HIF构件HIF-2¿对体内EPO基因表达至关重要的人。尽管现在已经确认了HIF-2缺在EPO调控中的重要作用，但导致体内暂时性EPO基因表达的因素或贫血患者中EPO基因表达异常表达的因素仍然知之甚少。我们最近确定了影响EPO调控的HIF-2信号传导的新型机制。创始HIF成员HIF-1的活性主要由蛋白质水平的变化控制，蛋白质水平的变化是由HIF-1蛋白的氧依赖性翻译后修饰介导的。然而，尽管HIF-2¿蛋白经历了相同的氧依赖性后翻译后修饰，但该机制并不是控制HIF-2信号传导的唯一甚至主要机制。如果不是缺乏氧气，那么激活HIF-2？的分子触发是什么？我们的中心假设是缺氧会触发中间代谢的变化，以实现HIF-2的乙酰化。在初步数据中，我们表明HIF-2？的活性受两种翻译后修饰，乙酰化和脱乙酰化的控制。在初步研究中，我们确定了HIF-2¿乙酰化的分子和生化基础，称为乙酸酯开关，涉及中间代谢的变化以诱导HIF-2 ?，乙酰化和共激活因子募集。解密乙酸盐开关如何调节HIF-2信号传导将为正常的EPO调控提供新的见解，并将确定选择性的分子靶标，以调节贫血患者内源性EPO基因表达。