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: 8624508
• 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/8624508
• 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病症，当伴随其他疾病状态时，贫血是发病率和死亡率增加的潜在危险因素，尽管贫血的治疗方法在过去几十年中有所改善，但几乎所有当前的治疗方法都涉及推注促红细胞生成素 (epo)。成人肾脏和患有严重贫血的肝脏中产生的一种内分泌因子，非生理性推注促红细胞生成素会产生不良影响，包括可能增加血栓形成风险以及对身体产生不良刺激作用。了解 epo 的调节机制将使研究人员能够开发除 epo 替代之外的合理疗法。我们是第一个确定第二个 HIF 成员 HIF-2 的人。 ，对于体内 epo 基因表达至关重要，同时也是 HIF-2 的重要作用。尽管目前人们对 epo 调节的认识已被认识，但我们对体内暂时性 epo 基因表达或贫血患者中 epo 基因表达异常抑制的因素仍知之甚少，我们最近发现了一种影响 epo 调节的 HIF-2 信号传导新机制。 HIF-1 的活性是 HIF 的创始成员，主要由蛋白质水平的变化控制，而蛋白质水平的变化是由 HIF-1 的氧依赖性翻译后修饰介导的然而，虽然 HIF-2¿蛋白质经历相同的氧依赖性翻译后修饰，这种机制不是控制 HIF-2 信号传导的唯一甚至主要机制，如果不是缺氧，那么激活 HIF-2 的分子触发因素是什么？ ? 我们的中心假设是缺氧会引发中间代谢的变化，从而影响 HIF-2 的乙酰化。在初步数据中，我们表明 HIF-2¿活性由两种翻译后修饰（乙酰化和脱乙酰化）控制。在初步研究中，我们确定了 HIF-2 的分子和生化基础。乙酰化，称为乙酸开关，涉及中间代谢的变化以诱导 HIF-2¿破译乙酸开关如何调节 HIF-2 信号传导将为正常 epo 调节提供新的见解，并将确定调节贫血患者内源性 epo 基因表达的选择性分子靶点。