Dokument: Treatment of Diabetic Retinopathy through Stabilizing Neurovascular Microenvironment
| Titel: | Treatment of Diabetic Retinopathy through Stabilizing Neurovascular Microenvironment | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=51379 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20191028-142535-4 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Mr. Ou, Kepeng [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Dr. Schrader, Stefan [Gutachter] Prof. Dr. Wesselborg, Sebastian [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Diabetic retinopathy (DR) is one of the most severe clinical manifestations of diabetes and a major cause of vision loss in worldwide working-age adults. The hallmarks of diabetic retinopathy include the damage and subsequent reduction of pericytes and endothelial cells numbers, followed by thickening of the vascular basement and further to disrupt the blood-retina barrier (BRB). The main known contributors to the breakdown of the BRB are pro-angiogenic factors, especially, vascular endothelial growth factor (VEGF), mainly secreted by upregulation from the hypoxia-induced activation of retinal Müller cells. However, there are early stages of diabetes-induced retinal neurodegeneration, which include reactive gliosis with subsequent impairment of retinal neuronal function. These changes are observed before the onset of vascular abnormalities in human and mouse diabetic retinal tissue. Therefore, DR is widely recognized as a neurovascular disease, which is in contrast to its conventional perception as a merely vascular disease. In the recent years, considerable efforts have been made to find treatments for this condition. Studies have shown that hypoxic preconditioning (HP) can stabilize hypoxia-inducible factor-1alpha (HIF-1α) to regulate the hypoxic retinal disease. It has also been reported that neuropeptides exert functions through their multiple receptors are potentially important for consideration in developing new drug strategies.
The aim of this thesis was to investigate HP of retinal Müller cells and adjunctive Neuropeptide Y (NPY) and Substance P (SP) to stabilize and improve the health of neurovascular microenvironment. The effect of HP was assessed in detail, using several methods, including in vitro angiogenesis and vascular integrity models. In parallel, metabolism of Müller cells was assessed using Seahorse XF Cell Mito Stress Test. In the next series of my experiments, to interrogate the protective effect of SP and NPY in maintaining the retinal neurovascular unit, tight junction proteins expression and Vascular Permeability Image Assay were used to determine vascular integrity in vitro. The protective effect of SP and NPY on retinal ganglion cells (RGC) was also analyzed in ex vivo retinal explants. More importantly, the protective effect of the neuropeptides was further investigated utilizing in vivo murine diabetic models. The experiments revealed that the hypoxic response of retinal Müller cells promotes vascular permeability and angiogenesis through HIF-dependent upregulation of pro-angiogenic factors VEGF and angiopoietin-like 4 (ANGPTL4). HP had a robust effect decreasing HIF-1α stabilization in response to hypoxia. In turn, HIF-mediated transcription and secretion of pro-angiogenic factors were reduced. This protective mechanism was linked to the change in the retinal Müller cells metabolic status. It was also demonstrated that SP and NPY are neuroprotective, suppressing apoptosis of RGC induced by N-methyl-D-aspartate (NMDA), and protect against VEGF-induced microvascular leakage of the retina. Moreover, NPY showed neurovascular protection of DR in type 1 diabetic mice. These effects demonstrate the significant role of HP and that the modulation of neuropeptide transmitters (SP and NPY) levels can be a potential novel approach of treatment in maintaining neurovascular-unit homeostasis, and open up new therapeutic avenues for DR. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie | |||||||
| Dokument erstellt am: | 28.10.2019 | |||||||
| Dateien geändert am: | 28.10.2019 | |||||||
| Promotionsantrag am: | 22.08.2019 | |||||||
| Datum der Promotion: | 25.10.2019 |
