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。

基本信息

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
项目类别：
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

项目摘要

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.

贫血是一种常见的疾病，与显着的发病率和死亡率相关，特别是如果患有其他疾病，例如心力衰竭。重组技术的发展促红细胞生成素 (Epo) 是成人贫血期间肾脏和肝脏产生的一种促红细胞激素，彻底改变了贫血治疗。不幸的是，非生理性推注 Epo 给药也促进血栓形成、高血压，并可能促进癌症生长。出现这种情况的部分原因是外源性Epo的施用缺乏内源性Epo的正常反馈调节特征，甚至在红细胞增多之前就迅速下调。内源性 EPO 产生和铁的吸收受到应激反应性异二聚体转录因子的严格控制诱导因子 2 (HIF-2)，其作用受氧依赖性和氧非依赖性调节翻译后修饰（PTM）。氧依赖性 PTM 包括脯氨酰的羟基化由氧依赖性脯氨酰介导的 HIF α 蛋白特定元件中的残基羟化酶 (PHD)，一个由三个相关蛋白组成的家族，对 HIF-1 和 HIF-1 表现出差异识别 HIF-2 α 亚基。经过共同努力，PHD 抑制剂 (PHDi) 的开发最近已上市经过近二十年的开发努力，但其长期安全性仍然未知。这 PHDi 的作用机制涉及 HIF-2 信号传导的稳定和/或增强活性。然而，鉴于 PHDi 缺乏完全特异性，HIF-1 信号传导也可能被激活以及 PHD 蛋白与 HIF 本身的串扰。尽管 PHDi 可能代表与外源性推注 Epo 给药相比有所改善，但 PHDi 治疗仍必须严格控制因为它们也缺乏与控制内源性 EPO 产生相关的反馈行为。此外，由于这些药物最近才进入市场并被用于选择在世界各地区，与现实世界环境中使用它们相关的副作用现在才出现光。有报告称使用它们会增加血栓形成，并且至少有鉴于 HIF-2 的长期增加，理论上对铁过载发展的担忧肠道中的信号传导也可能刺激铁的吸收和利用。为了利用 Epo 表达的正常反馈调节特征，我们必须了解缺氧期间 HIF-2 信号如何在动态和时间意义上发生。一增强 HIF-2 信号传导的机制涉及循环乙酰化和脱乙酰化后翻译修饰。该过程中的限速步骤是提供乙酰辅酶A用于 HIF-2 的乙酰化，由乙酸依赖的乙酰辅酶 A 生成剂酰基辅酶 A 产生合成酶 2 (Acss2)。 Acss2 在缺氧的早期阶段活跃，此时细胞在应对这种环境压力。在这个提案中，我们将定义周围的相互作用组 Acss2 和 HIF-2 在常氧条件下以及早期和晚期缺氧时期。我们将还可以根据 HIF-2 如何作用的知识确定合理的药物治疗方法乙酰化/脱乙酰化完成，可用于治疗患有慢性贫血的小鼠患有慢性肾脏疾病。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
作者：
通讯作者：

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.