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Glaucoma, just as many other neurodegenerative diseases, triggers neuronal death and remained incurable, hence representing a heavy burden for the society. Therefore, there is a critical need for developing new therapeutic strategies to delay the progression of and, ultimately, cure neurological conditions. For decades, neuroscientists studying injuries and diseases of the CNS have largely focused on understanding the mechanisms of axon degeneration to identify new targets for axonal protection and regeneration. But recent data indicates that dendritic deficits represent an early feature of neurodegeneration, a phenomenon now called dendritic pathology and playing a key role in the pathogenesis of neurodegenerative diseases including glaucoma. Because dendrites are essential structures for neuronal communication and function, it is therefore crucial to protect or restore connectivity as well as axons of surviving neurons to improve patients' condition. In spite of this, the ability of injured neurons to regenerate dendrites remains largely ignored. The central hypothesis of the thesis is that: i) adult CNS neurons can regrow their dendrites after axonal injury, and ii) the identification of underlying signalling pathways would offer new therapeutic avenues to slow or prevent retinal ganglion cell death during ocular neuropathies such as glaucoma. In the first part of my thesis, I demonstrated that mammalian neurons are endowed with the ability to restore their dendritic arbor and synaptic connectivity. Using adult transgenic mice subjected to optic nerve axotomy, we have shown that retinal ganglion cells (RGCs) rapidly undergo dendritic shrinkage before cell death or axonal damage become visible. We also demonstrated that daily insulin, administered topically (eye drops) or systemically (intraperitoneal) after dendritic arbour shrinkage and prior to neuronal loss results in a robust regeneration of dendrites and successful reconnection with presynaptic targets. Moreover, insulin-mediated restoration of dendritic arbors extended neuronal survival and rescued lighttriggered retinal responses. Targeted loss-of-function experiments using siRNAs revealed that insulin-dependent regeneration requires both the activity of both mTOR complexes, mTORC1 and mTORC2 which act synergistically, mTORC1 promoting new dendritic branching to restore arbor complexity, while mTORC2 drives dendritic process elongation. In the second study presented in my thesis, we showed for the first time that morgana, a chaperone protein downstream of mTORC2, is expressed by RGCs and severely downregulated soon after axonal injury. We also demonstrate that morgana is required for successful insulinmediated regeneration of RGC dendrites and neuroprotection. Morgana specific knockdown using siRNA designed against morgana resulted in substantial alterations of dendrite elongation, without changes in arbor complexity. Further, we showed that AAV-mediated rescue of morgana expression selectively in RGCs promoted striking regeneration of dendrites and synapses. Hence, our findings identified a new role for morgana in the regulation of dendritic arbor morphology in adult mammalian neurons Collectively, the findings presented in this thesis contribute to a better understanding of the pathological mechanisms underlying RGC dendritic pathology and identified promising targets for the development of novel neuroprotective treatments for neurodegenerative diseases such as glaucoma.
Glaucoma is the leading cause of irreversible blindness worldwide. High intraocular pressure (IOP) is the most important risk factor to develop the disease. The retraction of retinal ganglion cell (RGC) dendrites is one of the earliest pathological changes leading to substantial functional deficits. We recently demonstrated that insulin, administered after arbor retraction, promoted remarkable RGC dendrite and synapse regeneration. Here, we asked the following questions: 1) is insulin effective at promoting RGC dendrite regeneration in experimental glaucoma? 2) is reduction of IOP sufficient to promote dendrite regeneration in the absence of exogenous insulin? 3) what are the signaling components downstream of insulin that stimulate RGC dendrite regeneration in glaucoma? Thy1-YFP mice, which allow visualization of RGC dendritic arbors, received an intracameral injection of magnetic microbeads to induce ocular hypertension. RGC dendrites were imaged by confocal microscopy and arbors were 3D reconstructed. Total RGC dendritic length and complexity increased in glaucomatous eyes treated with insulin to values similar to those found in intact non-injured controls, but not in eyes treated with brinzolamide, to lower IOP, or vehicle. RGCs were isolated by Fluorescence Activated Cell Sorting (FACS) from insulin- or vehicle-treated glaucomatous retinas as well as shamoperated controls, followed by RNA sequencing analysis (RNA-seq). Our data show a global decrease in transcriptional efficiency in glaucomatous retinas. In addition, we identified a number of key regulatory pathways potentially implicated in insulin-induced RGC dendrite regeneration including: the mammalian target of rapamycin (mTOR), glycolysis, fatty acid metabolism, DNA repair, and myc-targets. These data allow us to draw the following conclusions: 1) insulin promotes robust RGC dendrite regeneration in glaucoma, 2) IOP reduction alone is not sufficient to promote dendritic regrowth, and 3) multiple molecular pathways are activated during insulin-mediated regeneration. These findings support a critical role for insulin administration to restore RGC dendritic structure, and identify differential gene expression that might reveal novel therapeutic targets for glaucoma.
Retinal Neurons—Advances in Research and Application: 2012 Edition is a ScholarlyBrief™ that delivers timely, authoritative, comprehensive, and specialized information about Retinal Neurons in a concise format. The editors have built Retinal Neurons—Advances in Research and Application: 2012 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Retinal Neurons in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Retinal Neurons—Advances in Research and Application: 2012 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.
The Science of Glaucoma Management: From Translational Research to Next-Generation Clinical Practice bridges the gap between laboratory research and clinicians by bringing the latest promising research directly from researchers to clinicians long before they translate into clinical advances, and often before they are presented at conferences. Organized as a series of clinically relevant topics written by world-leading experts, this book summarizes the current state of laboratory and translational research and draws on the potential implications for day-to-day clinical practice. It offers new insights and mind-opening statements through contributions from some of the most respected glaucoma research groups. The book allows glaucoma specialists to explore novel ways to refine and rethink their practice based on the latest discoveries in basic sciences and breakthrough technologies, and to gain a better understanding on how their specialty is evolving and how research may shape tomorrow’s practice. Presents a detailed report on the latest translational research and breakthroughs that may transform glaucoma practice Overviews the specialty from a scientific and clinical point-of-view Written by world-renowned clinicians and researchers in the field of glaucoma Includes insights, opinions and recommendations from some of the most prominent scientists and ophthalmologists Covers hot topics and the latest technologies in glaucoma, such as minimally invasive glaucoma surgery, telemedicine, gene therapy, neuroprotection and artificial intelligence
Since their development a decade ago, human induced pluripotent stem cells (iPSC) have revolutionized the study of human disease, given rise to regenerative medicine technologies, and provided exceptional opportunities for pharmacologic research. These cells provide an essentially unlimited supply of cell types that are difficult to obtain from patients, such as neurons or cardiomyocytes, or are difficult to maintain in primary cell culture. iPSC can be obtained from patients afflicted with a particular disease but, in combination with recently developed gene editing techniques, can also be modified to generate disease models. Moreover, the new techniques of 3 Dimensional printing and materials science facilitate the generation of organoids that can mirror organs under disease conditions. These properties make iPSC powerful tools to study how diseases develop and how they may be treated. In addition, iPSC can also be used to treat conditions in which the target cell population has been lost and such regenerative approaches hold great promise for currently untreatable diseases, including cardiac failure or photoreceptor degenerations.
This book focuses on the concept of ocular rigidity, the biomechanical properties and hydrodynamics of the human eye. The basics of anatomy and physiology are explored and the relevant data for the clinician are emphasized throughout the book. The engineering aspects as well as the clinical interpretation are presented to provide context. Ocular Rigidity, Biomechanics and Hydrodynamics of the Eye summarises recent evidence on ocular rigidity, but also provides a complete presentation of the data so far. The authors have recently worked on ocular rigidity corneal and globe biomechanics and hydrodynamics and the new, up-to-date data on the subject are highlighted in each chapter. The aim is to provide the framework or the understanding of these parameters and to determine their relevance in health and disease. This book will be an essential read for all practicing ophthalmologists looking to gain a more in-depth understanding of this interesting area of research particularly in refractive surgery and glaucoma.
Mitogen-activated protein (MAP) kinase (MAPK) cascades are key signaling components that govern essentially all cellular processes evoked by any type of stimulation, and it has been well established that the malfunctioning of these cascades leads to various diseases including cancer, autoimmunity, and diabetes. In MAP Kinase Signaling Protocols, Second Edition, expert researchers fully update the popular first edition the key techniques used in the study of MAPK signaling cascades in various cellular contexts. This thorough volume explores essential topics such as activation and function of components of the MAPK signaling cascades, the study of MAPK cascades as transmitters of membranal receptor signals, structure-function relationships of MAPKs, studies on the regulation of MAPK cascades, the use of lower organisms, animal models, and human genetics in the study of MAPKs, as well as the study of MAPKs in specific systems and diseases. Written in the highly successful Methods in Molecular BiologyTM series format, chapters includes introductions to their respective subjects, lists of the necessary materials, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Comprehensive and cutting-edge, MAP Kinase Signaling Protocols, Second Edition aims to facilitate the study of MAPKs and allow for quicker progress in our knowledge of many vital cellular processes as well as devastating diseases.
Intracellular cell signaling is a well understood process. However, extracellular signals such as hormones, adipokines, cytokines and neurotransmitters are just as important but have been largely ignored in other works. Aimed at medical professionals and pharmaceutical specialists, this book integrates extracellular and intracellular signalling processes and offers a fresh perspective on new drug targets.