Organelle Trafficking In Health And Disease Of The Retinal Pigment Epithelium
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Organelle Trafficking In Health And Disease Of The Retinal Pigment Epithelium
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Author : Li Xuan Tan
language : en
Publisher:
Release Date : 2018
Organelle Trafficking In Health And Disease Of The Retinal Pigment Epithelium written by Li Xuan Tan and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018 with categories.
The retinal pigment epithelium (RPE) is a key site of damage in macular degeneration, which causes irreversible blindness in 30-50 million people globally. Our work aims to elucidate disease mechanisms and identify promising therapeutic targets. Using live-cell imaging, biochemical approaches and a mouse model of disease, this thesis examined the role of organelle trafficking in autophagy and complement regulation, two pathways implicated in macular degeneration. Autophagy is a major cellular clearance pathway essential for maintaining homeostasis in post-mitotic tissues such as the RPE. However, little is known regarding how autophagy is regulated in the RPE. Here, we showed that pathological accumulation of vitamin A metabolites in macular degeneration traps cholesterol in the RPE and inhibits both autophagosome biogenesis and autophagic clearance. Mechanistically, we determined that cholesterol activates acid sphingomyelinase (ASMase), causing increased generation of ceramide. This in turn promotes aberrant stabilization of microtubules and constraints autophagosome trafficking, preventing effective clearance of autophagic substrates. The work in this thesis also establishes a central role for organelle trafficking in regulating protective mechanisms against the abnormal activation of the complement system, which has been implicated in macular degeneration. These novel protective mechanisms in the RPE include accelerated recycling of the complement regulatory protein CD59 to the cell surface, and lysosome exocytosis-mediated membrane repair. Both protective mechanisms are impaired in diseased RPE due to alteration in organelle trafficking, leading to mitochondrial damage and oxidative stress upon exposure to complement. A key RPE function indispensable for vision is the phagocytosis and degradation of photoreceptor outer segments. The thesis characterized sequential interactions of outer segment phagosomes with autophagic machinery as the phagosomes traffic from the cell surface into the RPE. Moreover, outer segment phagocytosis activates transcription factor EB (TFEB), which regulates a vast arsenal of autophagy and lysosomal genes. Thus, the RPE may employ autophagy machineries for efficient clearance of phagocytosed outer segments. Altogether, these studies highlight the importance of organelle trafficking in RPE health and function. Importantly, this research revealed that removing excess cholesterol or inhibiting ASMase using FDA-approved drugs corrects organelle trafficking, thereby restoring autophagy and complement regulation in models of macular degeneration.
Live Imaging To Investigate Organelle Form And Function In The Retinal Pigment Epithelium
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Author : Gulpreet Kaur
language : en
Publisher:
Release Date : 2018
Live Imaging To Investigate Organelle Form And Function In The Retinal Pigment Epithelium written by Gulpreet Kaur and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018 with categories.
The retinal pigment epithelium (RPE) performs many functions that are indispensable for vision, such as recycling vitamin A for the visual cycle, and participating in the daily renewal of photoreceptors. Over time, vitamin A metabolites, called lipofuscin, accumulate within RPE lysosomes and are thought to compromise RPE and photoreceptor health and promote inflammation. The RPE is also an initial site of insult in blinding diseases such as age-related macular degeneration. Accumulation of lipofuscin is a feature of inherited macular degenerations and could also contribute to age-related macular degeneration (AMD); however, the mechanisms behind this are still under study. We have previously established that RPE with vitamin A metabolites have increased ceramide and defects in autophagic and endo-lysosomal pathways. In this study, we have investigated two consequences of ceramide accumulation: 1) increased biogenesis of early endosomes, due to ceramide-induced negative curvature and inward budding; and 2) altered organelle traffic due to ceramide-induced accumulation of acetylated microtubules. First, we have identified the mechanism by which ceramide accumulation in RPE with vitamin A metabolites leads to enlarged early endosomes. These swollen endosomes internalize and cleave the complement protein, C3, into its active component, C3a. The acid sphingomyelinase inhibitor, desipramine reduces ceramide levels in RPE with vitamin A metabolites, corrects early endosome defects, and prevents complement activation. Second, we have previously noted that RPE with vitamin A metabolites have defective autophagosome trafficking and autophagic flux. In this study, we investigated the role of histone deacetylase 6 (HDAC6), a tubulin deacetylator, in autophagy. We established that HDAC6 inhibition results in accumulation of acetylated microtubules and reduced autophagic flux and trafficking. It remains to be determined if acetylated microtubule accumulation in RPE with vitamin A metabolites is dependent on HDAC6 activity. Our approach is to study healthy and stressed RPE at a cellular and molecular level, using techniques such as high-speed live imaging of polarized primary RPE cultures and mouse models of inherited macular degeneration, such as the Abca4-/- model of Stargardt disease. Our studies have investigated the role of organelle morphology and dynamics in maintenance of RPE health.
Retinal Pigment Epithelium In Health And Disease
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Author : Alexa Karina Klettner
language : en
Publisher: Springer Nature
Release Date : 2020-01-01
Retinal Pigment Epithelium In Health And Disease written by Alexa Karina Klettner and has been published by Springer Nature this book supported file pdf, txt, epub, kindle and other format this book has been release on 2020-01-01 with Medical categories.
This book provides a contemporary resource on one of the major players in retinal diseases – the Retinal Pigment Epithelium (RPE). Throughout the book, the physiological and the pathological function of the RPE are covered on equal terms, to help readers to understand the RPE as a whole. Moreover, the development of RPE in diagnostics and therapy are covered, as well as some practical knowledge about RPE experimental models. Retinal Pigment Epithelium in Health and Disease highlights new findings of RPE research and includes the state-of-the-art knowledge of each RPE topic presented. This important feature sets this book apart from other publications, with the chapters following a design which leads from the general to the specific, to give a precise collection of the facts known. The chapters are written by well-known experts that are currently active in the field as consultants, basic scientists, and group leaders, providing expert guidance on the current aspects and future outlooks of this topic.
Mitochondrial Diseases
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Author : Eylem Taskin
language : en
Publisher: BoD – Books on Demand
Release Date : 2018-08-29
Mitochondrial Diseases written by Eylem Taskin and has been published by BoD – Books on Demand this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018-08-29 with Medical categories.
Mitochondria are crucial organelles for any cell type. Mitochondria take responsibility for not only energy production but also regulation of cell death, also called apoptosis; calcium storage; and heat production. Therefore, mitochondrial disease is implicated in the mode of action of many harmful factors for cells such as drugs and environmental contaminants, dysfunction of the oxygen transport system, malnutrition, intense exercise, and genetic variations. This book presents up-to-date knowledge about mitochondrial disease and its complex relation to some diseases such as cardiac failure, cancer, and Alzheimer's and Parkinson's diseases. This book will, therefore, be essential for readers who are interested in life sciences, especially in medicine.
Intraocular Inflammation
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Author : Manfred Zierhut
language : en
Publisher: Springer
Release Date : 2016-01-12
Intraocular Inflammation written by Manfred Zierhut and has been published by Springer this book supported file pdf, txt, epub, kindle and other format this book has been release on 2016-01-12 with Medical categories.
This well-structured and lavishly illustrated book is a comprehensive reference on intraocular inflammation that encompasses all anatomic forms, settings and etiologies. Individual sections are devoted to uveitis associated with systemic disorders, uveitis syndromes restricted to the eye, bacterial uveitis, viral uveitis, fungal uveitis, parasitic uveitis, uveitis caused by other microbes, traumatic uveitis, and masquerade syndromes. Chapters on the different forms of uveitis are in a homogeneous reader-friendly format, with identification of core messages, explanation of etiology and pathogenesis, up-to-date information on diagnostics and differential diagnosis and guidance on the most appropriate forms of treatment and prognosis. Helpful flow charts are included to assist in identification of potential underlying disorders and the reader will also have online access to one hundred informative case reports demonstrating the different courses of intraocular inflammation. The authors are world experts keen to share their vast experience with the reader. Intraocular Inflammation will be a valuable resource for all physicians who deal with patients with inflammatory eye disease.
Retinal Degenerative Diseases
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Author : Matthew M. LaVail
language : en
Publisher: Springer Science & Business Media
Release Date : 2011-12-21
Retinal Degenerative Diseases written by Matthew M. LaVail and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2011-12-21 with Medical categories.
This book will contain the proceedings of the XIV International Symposium on Retinal Degeneration (RD2010), held July 13-17, 2010, in Mont-Tremblant, Quebec, Canada. The volume will present representative state-of-the-art research in almost all areas of retinal degenerations, ranging from cytopathologic, physiologic, diagnostic and clinical aspects; animal models; mechanisms of cell death; candidate genes, cloning, mapping and other aspects of molecular genetics; and developing potential therapeutic measures such as gene therapy and neuroprotective agents for potential pharmaceutical therapy.
Apoptotic Cell Clearance In Health And Disease
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Author : Estee Kurant
language : en
Publisher: Frontiers Media SA
Release Date : 2018-12-27
Apoptotic Cell Clearance In Health And Disease written by Estee Kurant and has been published by Frontiers Media SA this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018-12-27 with categories.
Clearance of apoptotic cells is essential for proper development, homeostasis and termination of immune responses in multicellular organisms. Thus, cellular and molecular players taking part in the sequential events of this process are of great interest. Research in the last 20 years has indicated that specific ligands and receptors take part in the attraction of immune cells toward apoptotic targets and in the interactions between apoptotic cells and professional as well as non-professional phagocytes that engulf them. Moreover, phagocytosis of apoptotic cells (efferocytosis) leads to significant phenotypic changes in the engulfing cells suggesting that it is a major fate-determining event for phagocytes. Particularly, efferocytosis has an important impact on the inflammation-resolution axis as well as embryonic development and tissue morphogenesis. Deficiencies in these processes can result in health threats, such as autoimmunity, atherosclerosis, bone loss, obesity, infertility, neurodegeneration, fibrosis and cancer. This eBook brings together 24 original research and review manuscripts that cover various aspects of apoptotic cell removal during normal development and homeostasis as well as in tumorigenesis and regenerative processes following injury.
Tissue Barriers In Disease Injury And Regeneration
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Author : Nikolai V. Gorbunov
language : en
Publisher: Elsevier
Release Date : 2021-06-19
Tissue Barriers In Disease Injury And Regeneration written by Nikolai V. Gorbunov and has been published by Elsevier this book supported file pdf, txt, epub, kindle and other format this book has been release on 2021-06-19 with Science categories.
Tissue Barriers in Disease, Injury and Regeneration focuses on the molecular and cellular fundamentals of homeostatic and defense responses of tissue barriers, covering the damaging impacts and exposure to pathogens and engineered nanomaterials. Sections emphasize the role of mesenchymal stoma, vascular, epithelial, telocyte, myofibroblast, lymphoid and reticuloendothelial cells, along with reactions that bridge the effects of ambient factors, medical treatments, drag delivery systems with alterations in barrier integrity, tissue/organ functions, and metabolic status. Other sections cover the role of progenitor cells of different origins in the remodeling and regeneration of tissue stroma, vasculature of blood-tissue barriers, and more. Includes special emphasis on the role of mesenchymal stoma, vascular, epithelial, telocyte, myofibroblast, lymphoid and reticuloendothelial cells in the development of reactions that bridge the effects of ambient factors, medical treatments, drag delivery systems with alterations in barrier integrity, tissue/organ functions, and in metabolic status Examines the role of progenitor cells of different origins in the remodeling and regeneration of tissue stroma, the vasculature of blood-tissue barriers, and mucosa and external epithelium
New Insights Into Retinal Degenerative Diseases
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Author : Robert E. Anderson
language : en
Publisher: Springer Science & Business Media
Release Date : 2001-12-31
New Insights Into Retinal Degenerative Diseases written by Robert E. Anderson and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2001-12-31 with Medical categories.
Since 1984, we have organized satellite symposia on retinal degenerations that are held in conjunction with the biennial International Congress of Eye Research. The timing and location of our Retinal Degeneration Symposia have allowed scientists and clinicians from around the world to convene and present their exciting new findings. The symposia have been arranged to allow ample time for discussions and one-on-one interactions in a relaxed atmosphere, where international friendships and collaborations could be established. The IXth International Symposium on Retinal Degeneration was held on October 9-14, 2000 in Durango, Colorado and was attended by over 100 scientists from six continents. This book contains many of their presentations. Several events of note occurred at this meeting. First, thanks to the generous support of the Foundation Fighting Blindness, we were able to sponsor the travel of 11 young scientists from six countries. Most of them have contributed chapters to this volume. The response to the travel program was so overwhelming that we will make it regular feature of our meeting. This will allow other bright, young investigators to be introduced to the world experts who study retinal degenerations. Second, about 40% of the scientists who attended this meeting were there for the first time. We believe that this indicates a growing interest in retinal degeneration research and ensures that new talent will be attracted to this important area of investigation. The symposium received support from several organizations.
Lysosomes
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Author : Pooja Dhiman
language : en
Publisher: BoD – Books on Demand
Release Date : 2017-08-30
Lysosomes written by Pooja Dhiman and has been published by BoD – Books on Demand this book supported file pdf, txt, epub, kindle and other format this book has been release on 2017-08-30 with Science categories.
This book covers current advances in disorders associated with lysosomal function along with techniques to study its function. All chapters are complete in themselves but united under a common research study topic. This publication aims at providing a thorough overview of the latest research efforts by international authors on lysosomal diseases and opens new possible research paths.