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节。

• 批准号: 10589528
• 负责人: Joseph Anthony Garcia
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 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 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589528
• 关键词: Acetate-CoA Ligase; Acetates; Acetyl Coenzyme A; Acetylation; Acetylesterase; Acetyltransferase; Acute; Adenine; Adult; Anemia; Behavior; Biotinylation; Bolus Infusion; CREBBP gene; Case Study; Cell Nucleus; Cells; Chromatin; Chronic; Chronic Kidney Failure; Coenzyme A Ligases; Complex; Data; Deacetylation; Development; Diet; Disease; Dissociation; EP300 gene; Elements; Endocrine; Enzymes; Erythrocytes; Erythrocytoses; Erythropoietin; Exhibits; Family; Feedback; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Growth; Healthcare; Heart Diseases; Heart failure; Hematocrit procedure; Hormones; Hydroxylation; Hypertension; Hypoxia; Hypoxia Inducible Factor; Immune response; Iron; Iron Overload; Kidney; Kidney Diseases; Knowledge; Label; Length; Liver; Lung diseases; Malignant Neoplasms; Mammals; Marketing; Measures; Mediating; Medical; Modification; Morbidity - disease rate; Mus; Nuclear; Nuclear Localization Signal; Organ; Oxygen; Peripheral arterial disease; Pharmacotherapy; Phase; Post-Translational Protein Processing; Process; Procollagen-Proline Dioxygenase; Production; Protein Acetylation; Proteins; Recombinant Erythropoietin; Regulation; Reporting; Repression; Rest; Resveratrol; Role; SIRT1 gene; Safety; Signal Transduction; Specificity; Stress; Stroke; System; Testing; Thrombosis; Time; Transducers; Veterans; bHLH-PAS factor HLF; human disease; hypoxia inducible factor 1; improved; inhibitor; member; mortality; mouse model; normoxia; novel; recruit; response; side effect; transcription factor; uptake

Anemia is a common medical condition associated with significant morbidity and mortality, especially if present with other diseases such as heart failure. The development of recombinant Erythropoietin (Epo), a pro-erythrocyte hormone produced in adult kidney and liver during anemia, revolutionized anemia treatment. Unfortunately, non-physiological bolus Epo administration also promotes thrombosis, hypertension, and possibly cancer growth. This occurs in part because administration of exogenous Epo lacks the normal feedback regulatory features of endogenous Epo, which is rapidly down-regulated even before erythrocytosis is evident. Endogenous Epo production and iron uptake are tightly controlled by the stress-responsive, heterodimeric transcription factor Hypoxia Inducible Factor 2 (HIF-2), whose actions are regulated by oxygen-dependent and oxygen-independent post-translational modifications (PTM). The oxygen-dependent PTM include hydroxylation of prolyl residues in specific elements of the HIF alpha proteins mediated by oxygen-dependent prolyl hydroxylases (PHD), a family of three related proteins that exhibit differential recognition of HIF-1 and HIF-2 alpha subunits. Development of PHD inhibitors (PHDi) have recently come to market after a concerted development effort over nearly two decades, but their long-term safety remains unknown. The mechanism of action for PHDi involves stabilization and/or enhanced activity of HIF-2 signaling. However, HIF-1 signaling is likely activated as well given the lack of complete specificity for the PHDi as well as cross-talk that PHD proteins have for HIF themselves. Although PHDi may represent an improvement over exogenous bolus Epo administration, PHDi treatment must still be tightly controlled as they also lack feedback behaviors associated with control of endogenous Epo production. Furthermore, because these agents have only recently come to the market and are being used in select regions of the world, side effects associated with their use in real world settings are only now coming to light. There have been case reports of increased thrombosis with their use and there is at least a theoretical concern for development of iron overload, given that prolonged augmentation of HIF-2 signaling in the gut may also stimulate iron uptake and utilization. In order to leverage the normal feedback regulatory features of Epo expression, we must understand how HIF-2 signaling occurs in a dynamic and temporal sense during hypoxia. One mechanism for enhancing HIF-2 signaling involves cyclical acetylation and deacetylation post- translational modifications. A rate-limiting step in this process is provision of acetyl CoA for use in acetylation of HIF-2, which is generated by the acetate-dependent acetyl CoA generator, acyl CoA synthetase 2 (Acss2). Acss2 is active in the early phase of hypoxia when cells generate acetate in response to this environmental stress. In this proposal, we will define the interactome surrounding Acss2 and HIF-2 under normoxic conditions as well as under early and late hypoxia periods. We will also determine if a rational drug therapy approach, based upon the knowledge of how HIF-2 acetylation/deacetylation is accomplished, can be used to treat mice with chronic anemia associated with chronic kidney disease.

贫血是与明显的发病率和死亡率相关的常见医学疾病， 特别是如果出现其他疾病，例如心力衰竭。重组的发展 促红细胞生成素（EPO），一种在贫血期间在成年肾脏和肝脏中产生的促胸细胞激素， 革命性的贫血治疗。不幸的是，非物理学推注EPO给药 促进血栓形成，高血压以及可能的癌症生长。这部分是因为 外源性EPO的给药缺乏内源性EPO的正常反馈调节特征， 即使在红细胞增多症也很明显之前，它也会迅速下调。内源性EPO产生和 铁吸收受到应力响应性，异二聚体转录因子缺氧的紧密控制 诱导因子2（HIF-2），其作用受氧依赖性和氧无关的调节 翻译后修改（PTM）。氧气依赖性PTM包括羟基化的羟基化 由氧依赖性脯氨酰介导的HIFα蛋白的特定元素中的残基 羟化酶（PHD），一个三种相关蛋白质的家族，表现出对HIF-1和HIF-1的不同识别 HIF-2α亚基。 在一致之后 在近二十年中的发展努力，但他们的长期安全仍然未知。这 PHDI的作用机理涉及HIF-2信号传导的稳定和/或增强活性。 但是，鉴于PHDI缺乏完全特异性，HIF-1信号传导也可能被激活 以及博士蛋白对HIF本身具有的跨对话。虽然PHDI可能代表 对外源推注EPO给药的改善，PHDI治疗仍必须严格控制 由于它们也缺乏与内源性EPO产生的控制相关的反馈行为。 此外，因为这些代理人直到最近才进入市场，并被用于选择 世界的区域，与现实世界中使用相关的副作用直到现在才来 光。有病例报告说，血栓形成增加了，至少有一个 鉴于HIF-2的扩大长期增强，对铁超载的发展理论关注 肠道中的信号传导也可能刺激铁吸收和利用。 为了利用EPO表达的正常反馈调节特征，我们必须 了解HIF-2信号在缺氧期间的动态和时间含义中如何发生。一 增强HIF-2信号传导的机制涉及周期性的乙酰化和脱乙酰化 - 翻译修改。在此过程中，限制速率的步骤是提供用于用于 HIF-2的乙酰化，这是由乙酸依赖性的乙酰二氧化碳发电机酰基COA产生的 合成酶2（ACSS2）。当细胞在缺氧的早期中，ACSS2在细胞中产生乙酸 对这种环境压力的反应。在此提案中，我们将定义周围的互动组 ACSS2和HIF-2在常氧性条件下以及低氧期和晚期晚期。我们将 还要根据HIF-2的知识来确定有理药物治疗方法是否存在 乙酰化/脱乙酰化完成，可用于治疗与慢性贫血相关的小鼠 患有慢性肾脏疾病。

项目成果

The acetate/ACSS2 switch regulates HIF-2 stress signaling in the tumor cell microenvironment.

• DOI: 10.1371/journal.pone.0116515
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Chen R;Xu M;Nagati JS;Hogg RT;Das A;Gerard RD;Garcia JA
• 通讯作者: Garcia JA

Adenoviral targeting of gene expression to tumors.

• DOI: 10.1038/cgt.2010.1
• 发表时间: 2010-06
• 期刊: Cancer gene therapy
• 影响因子: 6.4

Mutual antagonism between hypoxia-inducible factors 1α and 2α regulates oxygen sensing and cardio-respiratory homeostasis.

缺氧诱导因子 1α 和 2α 之间的相互拮抗调节氧传感和心肺稳态。

• DOI: 10.1073/pnas.1305961110
• 发表时间: 2013
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Yuan,Guoxiang;Peng,Ying-Jie;Reddy,VaddiDamodara;Makarenko,VladislavV;Nanduri,Jayasri;Khan,ShakilA;Garcia,JosephA;Kumar,GaneshK;Semenza,GreggL;Prabhakar,NanduriR
• 通讯作者: Prabhakar,NanduriR

The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response.

• DOI: 10.1016/j.cell.2014.03.032
• 发表时间: 2014-04-24
• 期刊: Cell
• 影响因子: 64.5
• 作者: Puente BN;Kimura W;Muralidhar SA;Moon J;Amatruda JF;Phelps KL;Grinsfelder D;Rothermel BA;Chen R;Garcia JA;Santos CX;Thet S;Mori E;Kinter MT;Rindler PM;Zacchigna S;Mukherjee S;Chen DJ;Mahmoud AI;Giacca M;Rabinovitch PS;Aroumougame A;Shah AM;Szweda LI;Sadek HA
• 通讯作者: Sadek HA

Coordinate regulation of stress signaling and epigenetic events by Acss2 and HIF-2 in cancer cells.

• DOI: 10.1371/journal.pone.0190241
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Chen R;Xu M;Nagati J;Garcia JA
• 通讯作者: Garcia JA