Studies of Hypoxia Response and Regulation of Hypoxia-inducible Factor HIF-1 in Caenorhabditis Elegans PDF Download
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Author: Chuan Shen
Publisher:
ISBN:
Category :
Languages : en
Pages : 236
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Book Description
All aerobic organisms require molecular oxygen to generate metabolic energy for normal growth and survival. During evolution, multi-cellular organisms have developed and refined complex networks for adaptation to hypoxic environments at both systemic and cellular levels. Adaptation to hypoxia largely results from changes in the activity and expression of key proteins. These include proteins involved in increasing oxygen delivery to hypoxic tissues and proteins that facilitate glycolysis for anaerobic metabolism. The mammalian transcription factor hypoxia-inducible factor (HIF) is a master regulator of oxygen homeostasis. More than 100 target genes of HIF mediate broad systemic and local responses to hypoxia, including angiogenesis/vascular remodeling, erythropoiesis, glucose transport, glycolytic metabolism, and cell proliferation. Many human diseases such as myocardial ischemia, stroke, cancer, and chronic lung disease cause hypoxic stress, and HIF is a critical mediator for pathophysiological responses to hypoxia. Elucidating cellular and molecular mechanisms underlying regulation of HEF activity may enable novel therapeutic approaches. The C. elegans hif-1 gene is orthologous to mammalian HIF-alpha gene, and C. elegans has proven to be a powerful system for the study of hypoxia-inducible factor regulation and function. In this dissertation, I studied the role of HIF-1 in hypoxia response and initiated genetic studies to identify HIF-1 regulators in C. elegans. I demonstrate that C. elegans hif-1 regulates the majority of early transcriptional responses to hypoxia. My studies also provide clear evidence for HIF-1-independent pathways for adaptation to oxygen deprivation. Finally, I discovered a novel membrane-bound protein that regulates the activity of C. elegans HIF-1 in a potential negative feedback loop.
Author: Chuan Shen
Publisher:
ISBN:
Category :
Languages : en
Pages : 236
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Book Description
All aerobic organisms require molecular oxygen to generate metabolic energy for normal growth and survival. During evolution, multi-cellular organisms have developed and refined complex networks for adaptation to hypoxic environments at both systemic and cellular levels. Adaptation to hypoxia largely results from changes in the activity and expression of key proteins. These include proteins involved in increasing oxygen delivery to hypoxic tissues and proteins that facilitate glycolysis for anaerobic metabolism. The mammalian transcription factor hypoxia-inducible factor (HIF) is a master regulator of oxygen homeostasis. More than 100 target genes of HIF mediate broad systemic and local responses to hypoxia, including angiogenesis/vascular remodeling, erythropoiesis, glucose transport, glycolytic metabolism, and cell proliferation. Many human diseases such as myocardial ischemia, stroke, cancer, and chronic lung disease cause hypoxic stress, and HIF is a critical mediator for pathophysiological responses to hypoxia. Elucidating cellular and molecular mechanisms underlying regulation of HEF activity may enable novel therapeutic approaches. The C. elegans hif-1 gene is orthologous to mammalian HIF-alpha gene, and C. elegans has proven to be a powerful system for the study of hypoxia-inducible factor regulation and function. In this dissertation, I studied the role of HIF-1 in hypoxia response and initiated genetic studies to identify HIF-1 regulators in C. elegans. I demonstrate that C. elegans hif-1 regulates the majority of early transcriptional responses to hypoxia. My studies also provide clear evidence for HIF-1-independent pathways for adaptation to oxygen deprivation. Finally, I discovered a novel membrane-bound protein that regulates the activity of C. elegans HIF-1 in a potential negative feedback loop.
Author:
Publisher: Elsevier
ISBN: 0080497195
Category : Science
Languages : en
Pages : 867
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Book Description
The ability of cells to sense and respond to changes in oxygenation underlies a multitude of developmental, physiological, and pathological processes. This volume provides a comprehensive compendium of experimental approaches to the study of oxygen sensing in 48 chapters that are written by leaders in their fields.
Author: Robert C. Roach
Publisher: Springer Science & Business Media
ISBN: 9780306466960
Category : Medical
Languages : en
Pages : 466
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Book Description
Hypoxia remains a constant threat throughout life. It is for this reason that the International Hypoxia Society strives to maintain a near quarter century tradition of presenting a stimulating blend of clinical and basic science discussions. International experts from many fields have focused on the state-of-the-art discoveries in normal and pathophysiological responses to hypoxia. Topics in this volume include gene-environment interactions, a theme developed in both a clinical context regarding exercise and hypoxia, as well as in native populations living in high altitudes. Furthermore, experts in the field have combined topics such as skeletal muscle angiogenesis and hypoxia, high altitude pulmonary edema, new insights into the biology of the erythropoietin receptor, and the latest advances in cardiorespiratory control in hypoxia. This volume explores the fields of anatomy, cardiology, biological transport, and biomedical engineering among many others.
Author: Corinne Lenore Pender
Publisher:
ISBN:
Category :
Languages : en
Pages : 232
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Book Description
The transcriptional response controlling adaptation to internal and environmental hypoxia is broadly conserved in animals. The key mediator of this response is the transcription factor HIF (hypoxia-inducible factor), which is active only in hypoxia due to the function of its negative regulators, the prolyl hydroxylase EGLN and the E3 ubiquitin ligase complex recognition subunit pVHL. HIF drives transcription of hundreds of targets that promote hypoxia adaptation. Recent work has also described important and broad roles for HIF outside of the traditional hypoxia response, including functions in immunity, oxidative and other stress responses, and behavior; how HIF targets drive these aspects of animal physiology is poorly understood. In this dissertation, I describe genetic analyses of the nematode C. elegans that have provided insight into the function of HIF targets in regulating animal physiology and behavior. The EGLN family was defined by the C. elegans homolog, EGL-9. Prior to the identification of EGL-9 as a HIF hydroxylase, our laboratory discovered the egl-9 gene from studies of egg-laying behavior. egl-9 loss-of-function mutants, in which HIF is constitutively active, are egg-laying defective; the mechanism regulating egg laying downstream of HIF has been unknown. From a screen for suppressors of the egl-9(lf) egg-laying defect, we identified the gene cyp-36A1, which encodes a cytochrome P450 enzyme and is likely a direct transcriptional target of HIF. In addition to modulating egg-laying behavior downstream of HIF, CYP-36A1 controls expression of more than a third of HIF-upregulated genes and regulates multiple stress responses. A screen for suppressors of cyp-36A1(lf) identified the nuclear hormone receptor NHR-46. We propose that CYP-36A1 functions as a hormone biosynthetic enzyme for the ligand of this receptor, thus mediating gene expression changes that alter stress physiology and behavior. We also found site-of-action and genetic evidence for at least one additional pathway acting downstream of EGL-9 and HIF-1 to regulate egg-laying behavior. These studies have identified novel HIF effectors that broadly affect physiology and behavior in C. elegans, and reveal new avenues for future work on regulation of HIF-controlled biology.
Author: Robert C. Roach
Publisher: Springer Science & Business Media
ISBN: 1475734018
Category : Medical
Languages : en
Pages : 448
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Book Description
Hypoxia remains a constant threat throughout life. It is for this reason that the International Hypoxia Society strives to maintain a near quarter century tradition of presenting a stimulating blend of clinical and basic science discussions. International experts from many fields have focused on the state-of-the-art discoveries in normal and pathophysiological responses to hypoxia. Topics in this volume include gene-environment interactions, a theme developed in both a clinical context regarding exercise and hypoxia, as well as in native populations living in high altitudes. Furthermore, experts in the field have combined topics such as skeletal muscle angiogenesis and hypoxia, high altitude pulmonary edema, new insights into the biology of the erythropoietin receptor, and the latest advances in cardiorespiratory control in hypoxia. This volume explores the fields of anatomy, cardiology, biological transport, and biomedical engineering among many others.
Author: Robert Roach
Publisher: Springer Science & Business Media
ISBN: 0387348174
Category : Medical
Languages : en
Pages : 354
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Book Description
The 14th volume in the series will focus on cutting edge research at the interface of hypoxia and exercise. The work will cover the range from molecular mechanisms of muscle fatigue and muscle wasting to whole body exercise on the world’s highest mountains. State of the art papers on training at high altitude for low altitude athletic performance will also be featured.
Author: Constantinos Koumenis
Publisher: Springer Science & Business Media
ISBN: 146145915X
Category : Medical
Languages : en
Pages : 293
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Book Description
The collection of chapters in this proceeding volume reflects the latest research presented at the Aegean meeting on Tumor Microenvironment and Cellular Stress held in Crete in Fall of 2012. The book provides critical insight to how the tumor microenvironment affects tumor metabolism, cell stemness, cell viability, genomic instability and more. Additional topics include identifying common pathways that are potential candidates for therapeutic intervention, which will stimulate collaboration between groups that are more focused on elucidation of biochemical aspects of stress biology and groups that study the pathophysiological aspects of stress pathways or engaged in drug discovery.
Author: Kiichi Hirota
Publisher: Mdpi AG
ISBN: 9783036529127
Category : Medical
Languages : en
Pages : 200
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Book Description
Oxygen is an essential molecule in the production of adenosine triphosphate (ATP) in cells, and a lack of energy due to O2 deficiency makes the maintenance of biological functions and human life improbable. Since oxygen functions as the final electron acceptor in the series of ATP synthesis reactions in conjunction with oxidative phosphorylation in mitochondria, its deficiency causes the oxidation of a series of coenzymes, such as nicotinamide and flavin adenine dinucleotide, and the reduction in oxygen molecules to water molecules (H2O). Persistent deficiency has been believed to cause a loss of biological functions, even resulting in death. This classical view of oxygen has been completely revised over the last 20 years. Mammals do not have a mechanism for biosynthesizing oxygen in their bodies. In higher organisms such as vertebrates, which possess many organs, oxygen in the body is always "scarce,"; therefore, the dominant view is that organisms have evolved mechanisms to respond to the lack of this essential molecule (hypoxia), and actively use it to maintain bodily integrity. Anatomically complex, higher multicellular organisms are equipped with specialized mechanisms to enable all cells to obtain sufficient oxygen. The respiratory system consists of lungs, which provide oxygen to be transferred to hemoglobin in red blood cells, the diaphragm, other respiratory support muscles, and neuroepithelial cells that sense the partial pressure of oxygen. The cardiovascular system consists of red blood cells, an oxygen-carrying medium, the heart, the transport engine, blood vessels, and transport channels. The proper development and preservation of these systems requires the harmonious expression of thousands of genes. The transcription factor responsible for this gene expression is hypoxia-inducible factor 1 (HIF-1). In this Special Issue, we invited research and review papers on various areas of oxygen biology research that focused on the fundamental understanding of HIF signaling pathways and related gene expression profiling, as well as pharmacogenomic biomarkers, molecular targets driving the regulation of human physiology and pathophysiology, and validation in animal models. We have published six original papers and three review articles in this Special Issue. We hope that this Special Issue will reflect the current exciting research concerning HIFs and their applications in medicine and health science.
Author: Divya Padmanabha
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
The adaptive response to hypoxia is accompanied by widespread transcriptional changes that allow for prolonged survival in low oxygen. Many of these changes are directly regulated by the conserved hypoxia-inducible factor-1 (HIF-1) complex; however, even in its absence, many oxygen-sensitive transcripts in Caenorhabditis elegans are appropriately regulated in hypoxia. To identify mediators of these non-HIF-dependent responses, I established a hif-1 mutant reporter line that expresses GFP in hypoxia or when worms are treated with the hypoxia mimetic cobalt chloride (cobalt chloride). The reporter is selective and HIF-independent, in that it remains insensitive to a number of cellular stresses, but is unaffected by mutation of the prolyl hydroxylase egl-9, suggesting that the regulators of this response pathway are different from those controlling the HIF pathway. I used the HIF-independent reporter to screen a transcription factor RNAi library and identified genes that are required for hypoxia sensitive and cobalt chloride-induced GFP expression. Three mediators of the HIF-independent response zinc finger protein BLMP-1, chromatin remodeling factor LIN-40, and T-box transcription factor TBX-38 were isolated as mediators of the HIF-independent response. First, we show that mutation of blmp-1 renders animals sensitive to hypoxic exposure and that blmp-1 it is required for appropriate hypoxic-induced expression of HIF-independent transcripts. Further, we demonstrate that BLMP-1 is necessary for an increase of hypoxia-dependent histone acetylation within the promoter of a non-HIF-dependent hypoxia response gene. Additionally, we explore BLMP-1's role in two hypoxia-regulated physiological processes namely unfolded protein response and collagen formation. We also briefly investigate the role of LIN-40 in the hypoxia response.
Author: Robert C. Roach
Publisher: Springer Science & Business Media
ISBN: 1441989978
Category : Medical
Languages : en
Pages : 367
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Book Description
The International Hypoxia Symposium convenes biannually to bring together international experts from many fields to explore the state of the art in normal and pathophysiological responses to hypoxia. Representatives from five continents and 32 countries joined together in February 2003 for four days in the dramatic mountains of Banff, Alberta. As editors of the Proceedings of the International Hypoxia Symposia, we strive to maintain a 26 six year tradition of presenting a stimulating blend of clinical and basic science papers focused on hypoxia. Topics covered in 2003 include hibernation and hypoxia, hypoxia and fetal development and new advances in high altitude pathophysiology, oxidative stress and membrane damage, hypoxic regulation of blood flow, heat shock proteins in hypoxia, and future directions in hypoxia research. In 2003 we also had the privilege ofhonoring John W. Severinghaus as a friend, colleague, mentor and inspiration to many in the field. Tom Hornbein's personal tribute to John Severinghaus is the first chapter in this volume, followed by an entertaining update of the history of the discovery of oxygen written by John Severinghaus.
