Organelle Trafficking in Health and Disease of the Retinal Pigment Epithelium PDF Download
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Author: Li Xuan Tan Publisher: ISBN: Category : Languages : en Pages : 150
Book Description
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.
Author: Li Xuan Tan Publisher: ISBN: Category : Languages : en Pages : 150
Book Description
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.
Author: Gulpreet Kaur Publisher: ISBN: Category : Languages : en Pages : 87
Book Description
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.
Author: Alexa Karina Klettner Publisher: Springer Nature ISBN: 3030283844 Category : Medical Languages : en Pages : 351
Book Description
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.
Author: Manfred Zierhut Publisher: Springer ISBN: 3540753877 Category : Medical Languages : en Pages : 1530
Book Description
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.
Author: Nikolai V. Gorbunov Publisher: Elsevier ISBN: 0128227567 Category : Science Languages : en Pages : 208
Book Description
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
Author: Stephen H. Tsang Publisher: Springer ISBN: 3319950460 Category : Medical Languages : en Pages : 274
Book Description
This Atlas of Inherited Retinal Disorders provides a thorough overview of various inherited retinal dystrophies with emphasis on phenotype characteristics and how they relate to the most frequently encountered genes. It also meets the previously unmet needs of PhD students who will benefit from seeing the phenotypes of genes they work on and study. Further, because genetic-testing costs are quite high and spiraling higher, this Atlas will help geneticists familiarize themselves with the candidate gene approach to test patients’ genomes, enabling more cost-efficient testing. This invaluable atlas is organized into eight sections starting with an introduction to the basic knowledge on retinal imaging, followed by diseases listed according to inheritance pattern and disorders with extraocular manifestations grouped by defining features. This structure will be intuitive to clinicians and students studying inherited retinal disorders.
Author: John C. Carey Publisher: John Wiley & Sons ISBN: 1119432677 Category : Science Languages : en Pages : 1104
Book Description
MANAGEMENT OF GENETIC SYNDROMES THE MOST RECENT UPDATE TO ONE OF THE MOST ESSENTIAL REFERENCES ON MEDICAL GENETICS Cassidy and Allanson’s Management of Genetic Syndromes, Fourth Edition is the latest version of a classic text in medical genetics. With newly covered disorders and cutting-edge, up-to-date information, this resource remains the most crucial reference on the management of genetic syndromes in the field of medical genetics for students, clinicians, caregivers, and researchers. The fourth edition includes current information on the identification of genetic syndromes (including newly developed diagnostic criteria), the genetic basis (including diagnostic testing), and the routine care and management for more than 60 genetic disorders. Written by experts, each chapter includes sections on: Incidence Diagnostic criteria Etiology, pathogenesis and genetics Diagnostic testing Differential diagnosis Manifestations and Management (by system) The book focuses on genetic syndromes, primarily those involving developmental disabilities and congenital defects. The chapter sections dealing with Manifestations and Management represents the centerpiece of each entry and is unmatched by other genetic syndrome references. Management of Genetic Syndromes is perfect for medical geneticists, genetic counselors, primary care physicians and all healthcare professionals seeking to stay current on the routine care and management of individuals with genetic disorders.
Author: Matthew M. LaVail Publisher: Springer Science & Business Media ISBN: 1461406307 Category : Medical Languages : en Pages : 867
Book Description
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.
Author: Jos A.F. Op den Kamp Publisher: Springer Science & Business Media ISBN: 3642731848 Category : Science Languages : en Pages : 474
Book Description
Many individual aspects of the dynamics and assembly of biological membranes have been studied in great detail. Cell biological approaches, advanced genetics, biophysics and biochemistry have greatly contributed to an increase in our knowledge in this field.lt is obvious however, that the three major membrane constituents - lipids, proteins and carbohydrates- are studied, in most cases separately and that a coherent overview of the various aspects of membrane biogenesis is not readily available. The NATO Advanced Study Institute on "New Perspectives in the Dynamics of Assembly of Biomembranes" intended to provide such an overview: it was set up to teach students and specialists the achievements obtained in the various research areas and to try and integrate the numerous aspects of membrane assembly into a coherent framework. The articles in here reflect this. Statting with detailed contributions on phospholipid structure, dynamics, organization and biogenesis, an up to date overview of the basic, lipidic backbone of biomembranes is given. Extensive progress is made in the research on membrane protein biosynthesis. In particular the post- and co-translational modification processes of proteins, the mechanisms of protein translocation and the sorting mechanisms which are necessary to direct proteins to their final, intra - or extracellular destination have been characterized in detail. Modern genetic approaches were indispensable in this research area: gene cloning, hybrid protein construction, site directed mutagenesis and sequencing techniques elucidated many functional aspects of specific nucleic acid and amino acid sequences.
Author: Li Xuan Tan
Author: Li Xuan Tan
Author: Gulpreet Kaur
Author: Alexa Karina Klettner
Author: Manfred Zierhut
Author: Nikolai V. Gorbunov
Author: Stephen H. Tsang
Author: Helga Kolb
Author: John C. Carey
Author: Matthew M. LaVail
Author: Jos A.F. Op den Kamp