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.

贫血是一种常见的疾病，发病率和死亡率都很高，

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